CZ413491A3 - N-imidazolyl derivatives of bicyclic compounds and process for preparing thereof - Google Patents

Abstract

Compounds of the formula (I) <IMAGE> (I) wherein the symbol represents a single or a double bond; Z completes a single bond or is a -CH2- group; each of R1, R2, R3 and R4, which may be the same or different is (a) hydrogen; hydroxy; halogen; cyano; C1-C6 alkyl; C1-C6 alkoxy; a C2-C4 acyl or C2-C4 acylamino group; -SR', -N(R') (R''), -CH2OR', -COR or -CH2COR, wherein R is OR' or -N(R') (R'') and each of R' and R'', being the same or different, is hydrogen or C1-C6 alkyl; or (b) one of R1, R2, R3 and R4 is 5- tetrazolyl or a group selected from -COCH2OR', -CH=C(R')-COR and -X-C(R') (R'')-COR, wherein R, R' and R'' are as defined above, and X is -O-, -S-, or -NH-, and the others are as defined above under (a); one of R5 and R6 is hydrogen and the other is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or a phenyl or pyridyl ring, wherein the phenyl or pyridyl ring is unsubstituted or substituted by one to three substituents chosen from hydroxy and C1-C4 alkoxy; or pharmaceutically acceptable salts thereof exhibit pharmaceutical activity as vasodilators or blood platelet aggregation inhibitors. Additionally, these compounds and their pharmaceutically acceptable salts are useful in the treatment of migraine, diabetic microangeopathy, rheumatoid arthritis, hypertension, peptic ulcers, osteoporosis, angina pectoris, atherosclerosis and dislipidaemies.

Description

N-Imidazolyl derivatives of bicycls, their preparation and process

The invention relates to novel N-icidazolyl derivatives of bicyclic compounds, in particular N-imidazolyl derivatives of 3,4-dihydro-2H-1-tenzopyran. 2K-1-benzopyran, 1,2,3,4-tetrahydronaphthalene, 1,2-dihydronaphthalene, indane and indene, processes for their preparation and pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

It is known that some compounds having an imidazole skeleton, such as imidazole alone, 1-alkylimidazoles and 1- (2-isopropylphenyl) imidazole derivatives, are capable of inhibiting thromboxane A ₂ (TXAg) synthetase-frostaglandins, Vol. 13, no.

4, 611 (1977); Biochemical and Biophysical Research Communications, Vol. 80, No. 1, 236 (197S)].

However, since imidazole and 1-lower alkylimidazoles exhibit only a very weak TXA ₂ inhibitory effect, these compounds lack any practical use as a medicament.

Therefore, it is very important to obtain compounds that have a stronger and more specific inhibitory activity. effect on TXA ₂ 3ynthetase.

Recently, tulles have been prepared synthetically by other imidazolyl compounds, more specifically, N-iidazolyl derivatives of 1-chroms (U.S. Pat. No. 4,342,775) and N-imidazolyl derivatives of &gt; 2,3,3,4-tetrahydronaphthalene, indane and 2-substituted

However, 1-chroman (UK patent application 2,106,509 A), which exhibits potent anti-platelet aggregation activity, has no activity as α-β-TXA ₂ synthase inhibitors. Surprisingly, it has now been found that certain imidazolyl derivatives, although structurally related to those disclosed in U.S. Patent 4,342,775 and UK Patent Application 2,106,509 A, are potent selective inhibitors of TXAj synthesis, and creoma this also stimulators? GI ₂ synthesis. These2

- r. - · i '? · -Τ compounds are described ^- in this present invention, which additionally some jeou imidízolylové · derivatives exhibiting strong. hypolipasic activity but no activity on the TXA / FG system;

^; - 'i ¹ ' - wy / yý ;; .............

··· ’· - · - - · - '>':. * -. -. *; *;

' ^J: ' · - ^ 'Pre-phrases' of the present invention are the following compounds

- .v · ’· -.--.

(I) wherein the symbol represents a single or double bond;

completes a single bond or denotes an oxygen atom or a group -CE, -;

R p R 4, R 4 and R 4, which may be the same or different, denote. ..... it individually (a) hydrogen, hydrpxyskupinu, halo, cyano, C ^ -Cg alkyl, C »-Cg alkcxyskupinu, Cj-C ^ ^{acyl nsbo C} 2 ^-C 4 ^c y ⁱ '~ ^{ir" axis: u} .R * pin, -SR ', -K i -CH 2 OR' -OCR or -CJUCOR ', where R is \ -II C ... cl b'

-Otí -R or and each R 'and R ^W have the same or jeou \ .rozdílné R, are hydrogen or C₁-C₆ alkyl, or (b) jeder. among the substituents R 1, R ₂ , and R 4 is 5-tetrazolyl or "R". R 'is selected from -CCCHgOR', * -CH-C-3OR and -XC-CCR,

R 'wherein R, R' and E ⁿ have the above meanings and X is -C-, -S or -NH- and the other is as defined under (a);

.- 3-

one of a.Hg. is. hydrogen and the other is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 cycloalkyl, or a phenyl or oyridyl ring; the phenyl or pyrimidyl ring is unsubstituted or substituted. substituted with one to three substituents selected from -hydroxy; and; The C 1 -C 4 alkoxy groups are pharmaceutically acceptable salts thereof. The present invention encompasses all possible isomers (non-target and trans isomers and optical isomers) of the compounds of Formula I and mixtures thereof, and metatholic precursors of the compounds of Formula I.

Conventional numbering is used to identify positions in the compounds of Formula I, as shown in the following examples:

and

Λ .ř.

5)

T6)

Pharmaceutically acceptable salts of the compounds of formula Ϊ include addition salts, with inorganic acids such as nitric, hydrochloric, hydrobromic, sulfuric, perchloric and the like ^; phosphoric acid or organic acids such as acetic acid, propionic acid, glycolic acid, lactic acid, oxalic acid, malonic acid, malic acid, maleic acid, tartaric acid, citric acid, tenzoic acid, cinnamic acid, mandelic acid and soycylic acid; for example alkali metal hydroxides, especially sodium or potassium hydroxide, or alkaline earth metal hydroxides, especially calcium or magnesium hydroxides, or with organic bases such as glycolamines, preferably triethylamine. The alkyl, alkoxy and alkylthio groups may be be. branched or straight chain groups. .

The halogen atom is, for example, fluorine, chlorine or bromine, preferably chlorine to bromine.

^{The C} 1-6 alkyl group is preferably a C 1 -C 6 alkyl group.

group. ’

The C 1 -C 6 alkoxy group is preferably an alkoxy group.

especially a methoxy, ethoxy or iopropoxy group.

The term acyl in the acyl and acylamino groups refers to acyl groups derived from both saturated and unsaturated carboxylic acids, preferably pannic acids such as acetyl, propionyl and butyryl.

The C 5 -C 6 cycloalkyl ring is preferably cyclopropyl

or cyclohexyl, especially cyclopropyl.

When one or more of the substituents K ₂ , R 3 and R 3 is halogen, it is preferably chlorine or bromine.

When one or more of the substituents ‘R ^, Hg, R ^ á is Cj-Cg alkyl, it is preferably methyl, ethyl, isopropyl or tert-butyl. butyl. .

When one or more of R 1, R ₂ , ^and R 4 is acyl, it is preferably acetyl or propionyl.

When one or more of the substituents R p is R ₂ ⁹

R 4 is a C ₂ -C 4 acylamino group, one or more is an o-acetylamino or propionylamino group. _.

When R and / or R are C ^ -Cg alkyl, with it. Preferably ^ l "^ 4 ^2e and ^Currency methyl or ethyl. ^- - - When one of the substitutes. Rj ,. and R ^ represents -CCCHgOR *, it is preferably a group -C0CH ₂ 0H or -CCCH QÍCn ^ -C ^) alkyl, especially -COCHjOCH- or -COCHgOC ^.

One or more of R ₂ R ₂ , -R 4 - and R 8 is SR, for example -SH or -S (C 1 -C 4) alkyl, in particular methylthio, ethylthio or isopropylthio.

When one or more. R, R _2, ^and R @ 4 ^2na ^ i ^ -Βζ group it is preferably a · -KH2, -NHCH -NHC ^ ^, ^ -BCCH or -N (C 2 ^H 5 ) ₂ .

When one r.ebo more of R ^> ^ 2 '^ 3 ³ 4 ^R <3 -CHcCR ^from, one to .s. preferably o -CH ₂ O.H, -CH ₂ OC _{1, 3} or -CH ₂ CC ₂ H ₅ .

Is one or more of the substituents? _n , R ₂ , R 6 and R 6 are -COR, preferably it is carboxy or C 1 -C 6 alkoxycarbonyl, in particular methoxycarbonyl or ethoxycarbonyl,

or is aminocarbonyl or di (C1-C4 alkyl) aminocarbonyl, in particular dimethylaminocarbonyl or di-ethoxyethylaminocarbonyl.

When one or more of R 1, R ₂ , R 1 and R 4 is -CrCOR, it is preferably carboxymethyl or C 1 -C 6 ^{and 1-} methoxycarbonylmethyl; ^R 1, especially methoxycarbonylmethyl or ethoxycarbonylmethyl or is aminocartonylmethyl or (C 1 -C 6) alkylaminocarbonylmethyl, in particular dimethylaminocarbonylmethyl or diethylaminocarbonylmethyl;

When one of R 6, ^S 3 ^{θ denotes} -X-CJ-CCR ,. it is with you. f., ... ^{with a} roll -OC-CQR where R and R ". they are the same or different and are hydrogen, methyl or ethyl; hydroxy or 'C ^ -C ₄ alkoxy .. pina, s; preferably, methoxy-; or an ethoxy group, or R injured.

amino or C 1 -C ₄ alkylamino, especially methyl;

'-Amino or- ethylamino, -r.ebo represents di (C, _-C4) alkylamino, particularly dimethylamino or diethylamino.

R * i

When one of R 1, R 1, R 1, and R 3 is -CH = C-COR, R is preferably hydrogen, methyl or ethyl and R is preferably hydroxy, methoxy, ethoxy, amino, methylami, ethylamino, dimethylamino or diethylamino.

When R8 or R8 is C1-C6 alkyl, it is preferably alkyl, especially methyl or ethyl. . .

When R 8 or R 8 is C 1 -C 8 cycloalkyl, it is. this is preferably cyclopropyl.

When R 8 or R 8 represents a phenyl or pyridyl ring, the ring is preferably unsubstituted or, if substituted, is preferably substituted with one to three substituents selected from 2 hydroxy and C 1 -C 6 alkoxy, in particular currency. methoxycups,

Preferred compounds of the invention are those compounds of formula I wherein the symbol: ---- represents a double bond;

has the above meaning;

each of the substituents R 6, R 8, R 8, and R 8, which may be the same or different, denotes. .

(a *) hydrogen, hydroxy, halogen, C ₁ -C ₄ alkyl, C 1 -C ₄ alkoxy, -CH 2 OH, -COOR _, or or ( ¹ : ¹ , 2, 3, 4, 5, 6, 7, 8, 9, 9, 9)

-CCN <^ ^a

Wherein R and R are independently hydrogen or

C 1 -C 4 alkyl; or It) one of _{R ',} R₂, R₃ and R ₄ is C _{£ C4} acyl, -CHgCOCR

7>

fa

R _a

-OC-CCCR 1 -CC-CCK 1, CH = C-CCCR _b or • -, a; $ c

We-rv . -CH = C COK \ ^ R _fi and R _b above VYZ suck '·' .. '· _and--%; . „...- ..

. other - substitutions have the same meanings as defined under (a *); .... . - _:

And R 8 is hydrogen and the other is hydrogen, C 1 -C 6 -alkyl, -cyclopropyl. _Even _nsJ3.o_Xenylový or pyridyl ring unsubstituted or substituted by one and three substituents selected from bydroxy-Cg and C 'alkoxy; and

------ - pharmaceutically acceptable salts thereof.

More preferred compounds of the invention are those compounds of formula I wherein the moiety --- represents a double bond;

2-is an oxygen atom or a -CHg- group;

substituentň one of R, R 33 and R 4 is -COOH _and> wherein "R _and has ^_ ',, shora.uvedený importance and the others are independently selected from SKU-pInv-consisting of hydrogen and hydroxy; ,, one R ^. R ₂ , R _3, and R ₄ is -CNH ₂ , -C ^CH, -COCH ₃ , -CH ₂ COOR _and> ,

3.

R.

,and

-CH = C-COOR _b , -CH * C-CONH ₂ , -OC-COOR a _, or -CC-CCNH ₂ , wherein

R%

Rx

R _n and _R are as defined above, and - the others are-independence, le 2 selected hydrogen, and hydroxyl;

R 6 and R 8 are both hydrogen; and pharmaceutically acceptable salts thereof. Especially preferred compounds of the invention are those compounds of formula I in which

-symbol- - ~ r represents a double bond;

is oxygen or -CH 2 -;

£ I * »

Z one of

R, R _2, R _4, and R represents -CO-CCB-in, where NH or -03 _and Rv and R ^ and R ^ are as defined above, and ostatr.

they represent hydrogen; . , ',

Eg and R1 are hydrogen; with their pharmaceutically acceptable salts,

Particularly preferred compounds of the invention are also those compounds of formula I in which the symbol represents a double bond; . . -ý. ·. - .., - 7 .'-. . _; '

Z is a group; ^';; ~ · λ - · Η one of,, .íUý 5 and -CCE_, -Cl-L-1CC.1. or -CH = C-CCE- wherein E a, H are as defined above, and the substituents are independently selected from hydrogen and ^; hydroxy groups;

R8 and Eg are hydrogen; and pharmaceutically acceptable salts thereof.

h e, particularly preferred compounds of the invention are those compounds of formula I wherein the symbol represents a double bond;

Z is -C ^-J _; one of R 4, R 4, R 4 ^and R 4 denotes -COR 4, where R 4 is as defined above and the others are hydrogen; J

Eg and R 8 are hydrogen; and pharmaceutically acceptable salts thereof. Examples of preferred compounds of the invention:

3- (l-imidazolyl} -2H-benzopyran, 3- ^{1-l imidazol3 ^y l) -6-chloro-2H-benzopyran *.

3 '- (1-imidazolyl) ‘' 6-methoxyl-2H-1'-bisulfate,

4) 3 '(L-ÍEÍdazolyl) -6-kartoxy-2H-l-fcenzopyran,) ·' ^3- (1-imidazolyl) -5- (2-karboxyisopropóxy) -2H-benzopyran, 3- I 1 -imidazolyl) -5- (2-carboxyvinyl) -2H-1-benzopyran,

2-methyl-3-yl-imidazolyl) -6-methyl-2H-1-tenzopyran, 2-methyl-3-yl-imidazolyl) -6-carboxy-2H-1-tenzopyran, 2-methyl-3- (i - (2-azidazolyl) -7-carboxy-2H-1-benzopyran,

(10) 2-methyl-3- (1-imidazolyl) -6-carbamoyl-2H-1-benzopyran;

11) 2-methyl-3- (1-imidazolyl) -C- (N-cartoxyvinyl) -2H-1-benzopyran,

12) 2-methyl-3- (1-imidazolyl) -6- (2-carboyyisopropyloxy) -2H-benzopyran,

13) 2-isopropyl-1 ', 3'-imidazolyl-6-carbonyl-2H-1-benzopyran,

14) 2-methyl-3- (1-imidasolyl) -β-ethoxycarbonyl-2H-1-benzopyran,

15) 2-cyclopropyl-3 '(1-inadazolyl) -6-cartoxy-2H-1-benzopyran,

1)

2)

3)

6)

7) y-i 8)

C)

- 'i. ‘Q · ♦: ·

17)

-18) ^x 19)

20)

21)

2- (3,4-dimethoxyphenyl) -3- (1'-idazoyl) -6-methyl-2R; 1-benzopyran.

2- (3,4-diaphthalophenyl) -3'-imidazolyl) -6-borohydrin-2H-1-tetropyran _; '; ·:

^; 2-C4- (4-aminophenyl) -3'-imidazolazolyl-5,7-aryloxy-2H-1-benzopyran, and 3,4-dihydro-3- (1-imidazolyl) ) -6-Cyclohexy-1-tenopyran,

3,4-dihydro-2-methyl-3- (1-imidasolyl) 75-carboxy-1-. * ^ hehzopyran v. ,,. . 22) 3,4-hydroxy-2-methyl-3- (1-imiazolyl) -6- (2-carboxyvinyl) -1-benzopyran;

-23). 1,2-dibydro-37 (1-hidazolyl) naphthalene.

(24) 1,2-dihydro-3- (1-imidazolyl) -6-methoxynaphthalene;

25) 1,2-dihydro-3- (1-imidazolyl-7-methoxynaphthalene);

26,2,2-Dihydro-3- (1'-imidazolyl) -6-methoxy-7-bromonaphthalene,

27) 1,2-dihydro-3- (1-imidazolyl) -8-methoxynaphthalene;

28) 1,2-dihydro-3- (1-imidazolyl) -6-carboxynaphthalene;

29) 1,2-dihydro-3- (1H-imidazolyl) -6-carbamoylnaphthalene,

30) 1,2-dihydro-3- (1-imidazolyl) -6-ethoxycarbonylnaphthalene,

31) 1,2-dihydro-3- (1-imidazolyl) -o-hydroxymethylnaphthalene;

(32) 1,2-dihydro-3- (1-imidazolyl) -7-carboxynaphthalene;

33) 1,2-dihydro-3-yl-imidazolyl) -5-carboxy-naphthalene;

34) 1,2-dihydro-3- (1-imidazolyl) -5-hexafluoroalynaphthalene;

35) 1,2-dihydro-3- (1-imidazolyl) -6-ethoxycarbonylmethyloxynaphthalene, ............. ......

36) 1,2-dihydro-3- (1-imidazolyl) -5- (2-ethoxycarbonylisopropoxy) naphthalene;

37) l, 2-dihydro-3- (l-iaiÍGa2olyl) _-6-l karboy.yir sthyloxynaftaIsn,

38) 1,2-dihydřb-3- (1-imidazolyl) -6- (2-propoxy karboxyisopi ^l) 7

r.aftalen,

39) 1,2-dihydro-3- (1-imidazolyl) -6- (2-carboxy vinyl) -raftalene,

40) 1,2-dihydro-3-β-imide (Zolyl) -6- (2-ethoxycarbonylmethyl) naphthalene;

41) 1,2-dihydro-3 (1H-azezolyl) -o-hydroxy-7-acetylphthalene,

42) 1,2-dihydro-3- (1-imidazolyl) -5-hydroxy-7-carbonynaphthalene, 43) 1,2-dihydro-3- (1-imidazolyl) -6-tert-butyl-7-hydroxynaphthalene ,

-ΊΟ-

(44) 1,2-dihydro-3-yl-2-olyl) - 6.-karto: -: diethylenetephthalene,

45). Ix-dlhydro-J-11-inadazolyl-S-1-naphthalene,

46) 1,2,3,4-tetrhydro-2-yl-1 H -pyridyl-7-carboxynthalene,

... .47) -1,2,3,4-tetrahydro-2- (l-iaifiazolyl) -5-ksrbcx3 ^of neftelen,

(48) .alpha., .beta.-1- (2-hydroxybenzyl) -7-naphthalene; , G '.'.- ·· <? · ·;

. . 49) 2- (1-azidazolyl) -5-5-carboxylic acid;

• ϊ; their pharmaceutically acceptable salts and, where appropriate, their C1-C4 alkyl esters.

The structural formulas of the above compounds are indicated by VA-ahor in the following table according to their sequence numbers:

<.

'. ·· '' 'Μ;

- · / - '#' '· Χ •'. '·> ·

Λ. -

51ouS. _ř Z · * 2 ‘· * 3 · * 4 * 5  'Zasfca' e: - ! - 1 -O- '/ · I 'h; ·, H H H  H> “7” x H ·· L ·, '·> ’·>. . double ? 2 Τ'-O- Hř -; Cl  H Ή '  H? ·· < - ..? double , 3 -0- H and ^KH 3 H H . H H double 4- -0-. H- ___COOH. H H H ' -H double 5 -P- H ch ₃ O-C-COOH ch ₃ H H H H double ...... 6 '': -0- H CH = CH-COOH ' H H : H H double - —0- -H- ~ «H _á - ... H— - ^CH 3 ~ -double ” 8 '-0- H COOH '' H . _H : H ch ₃ double ~ 9 "-O- “Η” ČOOH ⁴ “ H H ^Cí1 3 double 10 -0- H CONH ₂ H H H ^tH 3 double 11 .......... '-O- H ch = ch-coh ” ...... <, Au H H ^CH 3 double 12 -0- H ch ₃ O-C-COOH ^H 3 H H H ^CH 3 double 13 . -0- H. . CÓÓH H H H i-Pr double! 1

/ - />. 12-- ·, <

31o u ’ OF »- ’M * · . ' * ² ý * 3. . ^S 4 -*with s ₆ - : 7a hundred 1 1 j. 14 -0- H COOEt H. H l H < ^CH 3 1 double 15 5 ^: -0 * ^: ·. * ť. H- - H- _; H ' H / i / cy-Pr - / double- 16 ' '-0- »» r H ^: 0CH ₃ H ~ h '~~ H ^r 'Ph (374OCHp') double 17 -0- H OH. H H h Ph (3,4-OH) double 18 . • -0- • H COOH> H H H . 3-Py. double 19 Dec -0- OH OH H. H Ph (4 OH) double 20 May -0- H COOH ' H H H H .simple 21 -0- H COOH H, H H ^CH 3 one- • breath 22nd -0- H CH 3 CH-COOH H H H ’ ^CH 3 one- spirit 23 • ^CH 2 ' H H H. H H . Ή. double .24 -ch ₂ - H OCH ₃ H H H H double 25 -CH ₂ - H H OCH ₃ H H H : .ovo-jna 26 -ch ₂ . H . ^0CH 3 Br H H . H double 27 Mar: -CH ' ₂ - H H H och ₃ H. H 1 1 double j '1

Λ ·

ŠLouč OF •IN * 3 «4 IN ! ^R 6 ' i / azca 42. 'ί ‘ : ^ch 2 * -1 '.. -t -, OH \ V i COOH_ t - H H H ·· • i: i - : dvpjná .‘4 * - '43 ^ Hj '? ř H £? ' - <S ' , 1 .double 44 - · * - '-"F H ch ₂ cooh 6 H H H H double ’...... 45 Ř -C'h ₂ - • ’Ά H H ’~ H COOH H • H and 1 double 1 46 -ch ₂ - H COOH H H H H 1 one- spirit 47 -CH ₂ - H H COOH H "  : »· jeden- '! spirit i £! 48 • ^CH f H CH = CH-COOH H H H H. : '1 simple ''. | ⁴⁹ direct in and out of ba H COOH H H H H double • i ». 50 Direct ^{: take} H , '-v CH = CH-COOH H H H. H double

..: ar

The abbreviations i-Fr, cy-Fr, t-3u, rh, Fy, and Et mean unityl isisopropyl, cyclopropyl, tert-butyl, phenyl, pynoyl and the like.

According to the present invention, they are the most preferred. X; s of the compound -7% - ·· <“'. ^; 2-Dihydro-3- (1-imidazely-4-carboxynaphthalene, alkyl esters), and pharmaceutically acceptable salts thereof;

1,2-dihydro-3- (1-imidazolyl) -6- (2-carboxyisopropoyl) naphthalene

-? · - C ^ -C ^ ^- alkyl esters and pharmaceutically suitable salt thereof;

·· ^-:. · '1 ^ 2-dihydro-3- (l-imino-dagol :, ^T I) -6-naphthalen-karbamoylnef and pharmaceutically acceptable salts thereof.

The compounds of the invention may be prepared by a process comprising;

a) converting a compound of formula II

in which

R 1, R ₂ , R p, R g, R g and Z have the meanings defined above and 16 is hydrogen or an acyl group, to a compound of formula I in which K g, R g, R _a , R g, S g and Z are as above defined meanings and the symbol --- means a double bond, or

b) reduction of a compound of formula II as defined above to give a compound of formula I wherein R 6, R 8, R 8, R 8, R 8, R 8 and Z have the above meanings and the symbol - represents a single bond;

c) reducing the compound of formula III

«.

- 15 - (III)

in which........

41 ^fi ^ 5 »· BGA ² have the above mentioned, meaning '· give a compound of formula I wherein R₅, R₆, 3 R, 4 ^{R» S} 5> and Rg 2 are as defined above and symbol-- -means single bond, or <

d) reducing the compound of formula IV

(Iv) in which ... ........ .....

R ^, Rg, R ^, R ^, R ^, Rg and R mají have the previously defined meanings to give a compound of formula I wherein R Ry, Rg, R ^, R ^, R ^, Rg and · have. the aforementioned meanings and the symbol - denotes a single bond and, if necessary, the compound of formula I is converted into another compound of formula I, and / or '. v. if desired, the compound of formula I is converted into a pharmaceutically acceptable salt thereof, and / or, if desired, the salt is converted to the free compound; and / or. if desired, the mixture of isomers of formula I is separated into individual isomers.

When M in the compound of formula (II) is an aryl group, it is, for example, a C8-C18 carboxylic acyl group, in particular ethyl, or it may be mesyl or tosyl. group.'

Conversion of a compound of formula II to a compound of formula I 'according to process a) above can be carried out in the presence of a suitable solvent, such as glacial acetic acid, of the mixture.

- 17 acstanftydride with pyridine, diaethylformaaid (B?) Or sulphate. oxide (DkSO); or benzene in the presence of appropriate amounts. even catalytic solids, strong acids such as concentrated H ₂ SO ₄ , HCl; or an β-olefin sulfonic acid, at

- ^ -téplótách vjrpzsahuíodlasi; $ ^Q: C'až ° -.po boiling. The same conversion can also be achieved by heating the compound of formula IX with a reflux condenser while boiling in concentrated acids, for example hydrochloric or hydrobromic acid. When in ^- a compound of the formula II M ^- Acyl groups, especially d-on-acetate Ib-V-E - - EŮže lehr-r eakce.provédět rovněž- pyrolysis at temperatures in the range of preferably from about 200 ° C to about 30 ° C. The reduction of the compounds of the formulas II, II 'and IV to the compound I' by the process of b), c) and d) can be carried out, for example, by catalytic hydrogenation in the presence of a suitable catalyst, e.g.

platinum / palladium, PtO ₂ , ruthenium, or Raney nickel in a suitable solvent, preferably selected from the group consisting of methanol, ethanol, acetic acid, cyclohexane;

three-hexane, ethyl acetate, benzene or toluene, whereby the procedure is at a pressure in the range atmospheric to _IR printout pressure of about 30 atmospheres and at, a temperature in the range room temperature to about 100 C. A compound of formula II, · wherein thi means tosyl. or mesyl, can be reduced, in particular, in an anhydrous aprotic solvent, preferably in diethyl ether or tetrahydrofuran (THF). The compound of formula III can be reduced according to the procedure of the invention, i.e. zinc amalgam in hydrochloric acid.

If desired, the compound of formula I can be converted to another compound of formula I. These optional conversions can be carried out by methods known per se.

Thus, for example, a compound of formula I in which one or more of. @ 5 substituents, R · _2> and R ^ is hydrogen, to convert the compound of formula I in which one or more of R₄,

R ₂ and R .značí halogen atom, e.g. chlorine nebo.brom, by reaction with chlorine or bromine in the presence of a Friedel-Craft3ova catalyst, preferably AlCl ^ -při- whereupon they. proceeds, in a suitable solvent, e.g., CH 2 Cl 2

- ιε and _2> R £ snamer.s _R4 is hydrogen, can be converted in a compound of formula-.1, in which no one more of R ,, R ", R, and phi ₄ indicates. '. By alkyl, by means of a Friedel-Crafts reaction, for example by reaction 3 '-':

) C ^ -Cgť / aikylhalogehídemy-s-preferably -chloridembromidem 'or jodidén,' Hebo ~ ák; '// JV \ ^<' <· '·' -. ^Λ

b) C Cg'alkoholem in a suitable solvent, e.g. nitrobenzene or C LCLO _O or CS. .. '?

'v' '

In both cases (a) and (b), the tangent reaction is in the presence of a suitable amount of Friedel-Crafts catalyst such as AlClp ZnCl ₂ or EF 4; and when a C 1 -C 8 aliphatic alcohol is used, also in the presence of a strong mineral acid such as HF, HClO 4 or, if desired, in concentrated H 2 SO 4 or concentrated H 2 PO 4 without additional solvent, at temperatures ranging from room temperature up to 100 µC.

A compound of formula I wherein one or more of R 1, R 2, R 3 and R 2 is a C 1 -C 6 alkoxy group can be converted to a compound of formula I wherein one or more of R 1, R 2, R 3 and R 3 is hydroxyl group by following conventional procedures well known in organic chemistry. For example, treatment with a strong mineral acid such as HCl, HBr, Kly. preferably HBr, at a temperature in the range of from 30 ° C to boiling point, preferably at boiling point, or by treatment with a Lewis acid such as AlCl 4 or EF 2 in a suitable solvent such as CH 2 Cl 2 or nitro-benzene at temperatures ranging room temperature range up to £ C ° C. A compound of formula I containing an esterified carboxyl group can be converted to a compound of formula I containing a free carboxyl group by alkaline or acid hydrolysis, at temperatures ranging from room temperature to about 100 ° C.

A compound of formula I containing a free carboxyl group can be converted to a compound of formula Ί containing, an esterified carboxy group by esterification, e.g. via a corresponding acid halide, e.g. chloride, by reaction with an excess of a suitable C 1 -C 8 alkyl alcohol, or by direct esterification using acidic catalysis i.e. in the presence of dry Cl or SOC1 ₂ or BF ^ -etherátu.

The compound of formula I containing a carbamoyl group. can be converted to a compound of formula 1 containing free

a carboxy group by hydrolysis, preferably by acidic hydrolysis, in a suitable solvent; such as water, or by a process according to the invention, by treating with an aqueous-acidic or inorganic acid; ^: H ₂ SO ₄ , at temperatures ranging between room temperature? And -1OC? ^Low: 16 ° C. ,,. . - ..

A compound of formula I containing free carboxylic acid group or esteriíikovanou can be converted to a compound of formula I containing the ^{group.-CONRÍR,;} wherein 4 and 3 have the meanings given above ·

Accordingly, the conversion of the esterified carboxyl group to the corresponding amide can be carried out by direct reaction with ammonia or a suitable amine in a suitable solvent, e.g., ether or benzene, or the like. using an excess of the amine as solvent. . .

at temperatures ranging from room temperature to about 50 ° C. , ......- - · - ··

The 'free' carbox group 's will not dry or be able to be carried out via an intermediate reactive derivative, which may or may not' isolate '.

In tne t er di Arnie .reaktiyním ^- diFivátem mohouTbýtžWti VHI ^- "esters, e.g. NOG-phenyl esters, or - N-hy drcxysukcininid- :. esters, acid halides, preferably chloride, mixed anhydrides such as ethoxycarbonyl or tert-butylcarboran anhydrides,

Or reactive intermediates obtained in situ by reaction of an acid

with dicyclohexylcarbodiimidec or carbonyldiimidazole.

Reactive intermediates obtained; by conventional routes such as those used in peptide synthesis, are reacted with ammonia or an appropriate amine in a suitable solvent or with an excess of the amine itself at temperatures ranging from about -10 ° C to about 50 ° C.

A compound of formula I wherein one of & R _2, £ ³ ^ 4 represents a free sb unitized carboxy, especially lower alkoxycarbonyl groups, can be converted into a compound of formula I wherein fij, R _2, S ^, and R ₄ represents a CHgCK group, by reduction by conventional means, preferably with LiAlH 4 in a suitable solvent, for example ethyl ether or ΤΗΓ.

A compound of formula X in which R 1, R ₂ , ^{and A} ₁ - is a free or esterified kerboxyl group, in particular a lower alk-

, .ve that * Ř ‘-: lá; ' 3? Have. The aforementioned meanings, by reduction first, of the free or non-esterified carboxy groups, to the form of the group, then. The aldehyde obtained is condensed with the desired phosphate acetate or or phosphonacetate followed by the Witting or Horner-Emmons procedure, or additionally, if R is 7 hydrogen, by condensation of the above aldehyde β.

with diethyl malonate, followed by a melon synthesis procedure, then heating the obtained malonate with a strong mineral acid. lines to make. hydrolyzed and decarboxylated. Ϊ.

The abovementioned reduction to the aldehyde can be carried out by:

(a) discharging from an esterified carboxyl group using diisobutylaluminum hydride (DIBAH) or diaminoaluminum hydrides;

b) exiting from the free carboxy group using bis- (4-methylpiperazinylaluminum hydride in THE) or diisobutylaluminum hydride or diaminoaluminum hydrides;

c) removal from the free carboxy group previously converted to the acid chloride by conventional means, e.g. by SOCl ₂ , reduction of lithium trit-butoxy-aluminum hydride chloride or conventional hydrogenation according to the Aosenmund process using a poisoned platinum catalyst or using tributyltin hydride. . '

The above-mentioned ittig condensation can be carried out. for example, with (Q) ₂ -F-C-COCR *, wherein R 1 is phenyl or lower alkyl, R has a lower alkyl group. .

and S * has the same meaning as above, preferably with ethyl or ethyl acetate, preferably in 8%, preferably in diaethoxyethane, or THE or DL, S, at the temperature moving. in the range of room temperature to about 60 ° C. An analogous Horner-Wittig process can be carried out e.g.

: · '* · /,.Τ.Ά

by hydrolysis and decarboxylation which can be carried out by boiling in a suitable acid, for example concentrated HCl.

Compound of Formula I in ketet ¹

free or esterified carboxy group or carbamoyl group can be converted to compounds ^of: Formula-I wherein one of R and E ^ represents 5-tetrazolyl group, by first converting a carboxyl or carbamoyl group in the CN, then-the resulting nitrite reacted with a NaN 2 - or a mixture of C 1 H 3 COOH / tert -BuOH to give the 5-tetrazolyl derivative of the formula I.

The above niobium is foggy. gain and * 7 directly from an inclusive carboxyl group-a-to-r-reaction with a chloro-sulfonyl isocyanate followed by decomposition by heating, in B 1? the corresponding chlorosulfonylamide;

b *) directly from the carbamoyl group by dehydration with chlorosulfonyl isocyanate or POCl 4 or dicyclohexylcarbodiimide (DDC);

- 22 Her? I * / ' ^s ,

-C-C-C20J, or -C-C-CC-Kf or -S-C-CCCA or

I I \ I

Λ,

J 's: ·'^; S-CH-CONC1-, 1kdeX, a. R; they have the above-defined definitions. * · '· »4 ... C * U» ¹¹ · · <''.'7' ............ '''............'.

“£”> and .- * · - nacy, reaction. a compound of formula A * -C-CCCR 'nel

T ^a

V-C-CON < *.

Wherein A * represents a halogen atom, preferably chlorine or bromine, or an active ester group, preferably a tosylate group, in the presence of a suitable base in a suitable solvent, e.g. in the presence of tert-BuOK in tert-BuOH, or anhydrous of carbon monoxide, acetone or sodium hydride in DftF, at temperatures ranging from room temperature to boiling point. ·· '>; - ·· * ··

Optionally converting a compound of formula I into a salt thereof, as well as converting a salt. the free compound and the separation of the mixture of isomers into the individual isomers can be carried out by conventional methods.

Separation of a mixture of geometric isomers, e.g. cis and trans isomers, can be accomplished, for example, by traction crystallization from a suitable solvent or by chromatography, tin by column chromatography or high pressure liquid chromatography. III by well known methods, e.g. by treatment with an alkali metal borohydride, e.g.

Na 2 H 2 O, in a suitable solvent, e.g. methyl or ethyl alcohol, or a mixture of water and ethyl alcohol, or. by treatment with LiAlH 4 in a non-aqueous solvent such as diethyl ether or tetrahydrofuran at temperatures in both cases preferably between 0 ° C and boiling point for a reaction time ranging from 1 to 6 hours.

A compound of formula IX wherein L 1: is a residue of an active acid derivative; as mentioned above, -3e may obtain; by known methods; for example by reacting a compound of formula II,

- · ’. ·; wherein M 1 is hydrogen, even with a suitable acyl halide or sulfonyl;

halide, preferably chloride ^ / for example, with ^'w acetyl or tosyl or mesyl chloro idem · ee whereby reaction is carried out for example, in anhydrous pyridine or in an inert solvent; e.g.

♦. anhydrous benzene, if necessary in the presence of an equimolar amount of a base such as triethylamine at temperatures ranging from room temperature to about 60 ° C.

The compounds of formula (III) may be prepared, for example, by a process comprising:

a) reacting a compound of formula V or a derivative thereof

...... A'- -

(V) wherein R 6, R 8, R 6, R 6; R 1, R 6 and R 2 have the same meanings as defined above and A is a halogen or an active ester group, with imidazole or a salt thereof, or when denotes. in the compound of formula II, substituent 2 is oxygen, then also

b) reacting a compound of formula 71

_s v R, - »1 ^at Xj ¹ / N \ zí • Í7I) and/ • w \ CH · r »» ; X.; . in which n. have the above-mentioned meanings, 4 · 711

R ^ -CO-Rg

(II) wherein R 6 and R 8 are as defined above, or with it

They may be the same or different, individually denoting a C 1 -C 6 alkyl or R 1 together form a straight or branched C ₂ -C 8 alkylene chain.

The carbonyl group is preferably protected in the form of a γ-dioxalane group.

When A in the compound of formula (7) is a halogen atom, it is preferably chlorine or bromine and is an active ester group, preferably -O-tosyl or -O-mesyl.

The imidazole salt is preferably an alkali metal salt such as sodium or potassium, or a silver salt. The reaction of the compound of formula 7 or a derivative thereof with the imidazole or its salts is preferably carried out here.

a) in the absence of a solvent, preferably at a temperature comprised between room temperature and about 16 ° C and for a reaction time ranging from several minutes to about 20 hours, using, if necessary, an excess of imidazole or a salt thereof , or '

b) in the presence of a suitable solvent, preferably dimethyl-

minutes to about 12 hours, and 2a use when needed nsd

base, preferably triethylsmin.

Protection of the compound of formula 7 as a 1,3-dioxaline group. it may be carried out by the following well-known steps of &gt; 25 ', e.g. reacting a compound of vzorce'Vs .diethýleriglykolea přítomnosti'silní ^t 4norganických or organic acids, "i.e., / p ťoluenšuífóriÓvékyseliny, 'číiiiTse yield' corresponding 1 3-dioxolane; ie ^: 1,2 _r ethylenedioxy derivative Jak As stated above. '' Top-Jióďstřanújé sej clučáňíc i group with poyreakeii> imidazole - ⁷ · follow ing obvyklýmipostupyi- napři- treatment - dilute. aqueous inorganic acids. . \; The reaction of a compound of formula VI with a compound of formula 711 or a reactive derivative thereof, which may be, for example, a bisulfite addition compound, may be carried out using a suitable solvent, e.g. water, methyl or ethyl alcohol or acetic acid, or mixtures thereof. water, or if necessary using an excess of compound VII, preferably at a temperature ranging from about room temperature to the boiling point for a reaction time ranging from a few minutes to several hours. When the compound of formula (VII) is formaldehyde, i.e. 5 &apos; and is hydrogen, it may also be hydrogen. derivative paraformaldehyde or trioyymethylene. :.

The compounds of formula IV are covered by the general formula I, in which the symbol - represents a double bond, and can be obtained, for example, according to process a) above.

........... The compound of formula V, in which. A is a halogen atom, may be obtained by halogenation of the corresponding compound of formula VIII

(VIII wherein B 1, R 1, R 1, R 1, and 2 have the above meanings. Helogenation of a compound of Formula VIII to a compound of Formula V can be accomplished as follows:

a) an atechiometric amount of halogen, preferably bromine or chlorine, in a suitable solvent such as diethyl ether, methylene chloride, CHCl 3. CCl2, CSg- or acetic acid, at a temperature in the range of from about 0 ° C to about 10 ° Cf

b) by reaction with a stoichiometric amount of GUEr ₀ in a suitable solvent, n-and, e.g. ethyl acetate, at temperatures ranging from about 5 ° C to the boiling point;

(c) using a stoichiometric amount of sulfuryl chloride in

suitably dispersed, for example, by a meter of chlorine, chlorine or benzene, at temperatures; in the range of about room temperature to the boiling point.

In all cases a), b) and cj the reaction times are between

and 12 hours. A compound of formula V in which A is -O-tosyl or -O-mesyl, can be obtained by reaction of the corresponding alcohol, i.e. practically a compound of formula V in which, but only for this compound, A is hydroxy which is known or can be prepared by known methods with p-toluenesulfonyl halide or methanesulfonyl halide, preferably chloride. ’· '··

The reaction is preferably carried out in an anhydrous inert solvent such as acetone at a temperature ranging from room temperature to the boiling point.

The compound of formula VI can be obtained by reacting the compound

wherein IL, R ', 3', R and A have the above meanings,

X with an imidazole or a salt thereof, preferably an alkali metal salt, e.g. a sodium or potassium salt, or a silver salt.

The reaction may be carried out using the same reaction conditions as described above for the reaction between the compound of formula V and imidazole or a salt thereof. ;

Compounds of formula VII are known compounds.

Also, the compounds of formula IIIa are known or can be prepared by known methods from known compounds. For example, a compound of formula VIII, wherein λ · ', 3 _2, 3 3 ,, ^, phi., 2 e 3 have the' above meanings ,; it is possible to obtain cyclizing compounds (X)

, R ^, i? _c 2 and Rg have the above výsupiny kysnovou, carboxyl, (C ₇ -C Al '. ve.kterém R, R _£, • nsmy Rj and R? znamená'sk - ^ alkoxy) karbohylOvou - ^ eboks] n: pin ^ C.ORg., "in_the.S_fig_j5_at_a_hal-o ......'..... ... gene ....... ........

Cyclization of a compound of formula X wherein R? is an acidic, carboxyl or (C 1 -C 6 alkoxy) carbonyl group, may be accomplished by treatment with a conventional cyclizing agent, e.g., an anhydride. phosphoric acid, polyphosphoric acid, chloro-sulfonic acid or sulfuric acid, optionally in the presence of a solvent, preferably selected from the group consisting of:

benzene, toluene and xylene, at a temperature which can range from about 20 ° C to about 130 ° C. Cyclization of compound

-v-zor-en — X., _ in which S? is -CCR4 and Bg.s., as defined above, is preferably carried out using AlCl. in the presence of a suitable solvent, such as carbon disulphide, at temperatures in the range of about 0 ° C to about 50 ° C.

Compounds of formula IX and X are known or can be prepared by known methods starting from known compounds. When in compounds of formulas I, II, III, IV, V, VI, VII,

VIII, IX and X groups present which must be protected during the above reactions, e.g., amino, hydroxy, further carbosyl groups, etc., can be protected by conventional methods before the reaction occurs.

As. examples of protecting groups are those commonly used in peptide synthesis, for example, acetyl, benzoyl, tert-butoxycarbonyl, p-methoxyphenyl-4-alkoxycarbonyl, o-nitrophenylsulfonyl, dichloroacetyl protecting groups can be used to protect the amino groups.

For the protection of examples of acetyl, hydroxyl groups, nazzoyl, phenyloxy, tetrahydropyranyl, 3-methoxyethoxycethyl (KBI) or trialkylsilyl such as tert-butyldisethylsilyl can be used. Use tert-butyl, tenzhydryl and p-methoxybenzyl group ## STR6 ## ## STR2 ## X ·. Ý .-- 4

The protecting group is then at the end of the reaction. is removed in a known manner, for example by mild acid hydrolysis or mild catalytic reduction, for example with a catalyst, Pd / C at atmospheric. spherical pressure. .

The amino, carboxyl and hydroxyl protecting groups are. It is then removed at the end of the reaction, in a manner known per se. For example, if the amino protecting group is a monochloroacetyl group, it may be removed by treatment with thiourea; forms X6 and trifluoroacetyl groups can be removed by treatment with potassium carbonate in aqueous methanol and tritium. The latter group is treated with formic or trifluoroacetic acid. The carboxyl protecting groups may be removed for example. for example by mild acid hydrolysis or catalytic hydrogenation, e.g. by Pd / C at normal pressure.

For example, the hydroxyl protecting groups may be removed from mild reaction conditions, e.g., by acid hydrolysis.

The compounds of the present invention are selective, inhalers of Thromboxane A ₂ 'synthesis (TxAp and synthesis stimulators. Prostacyclin (FGI)).

The activity of No. 1 TxA 1 and PGX ₂ tulle synthetase was evaluated in vivo. For example, rats are given a single oral dose of compound and then sacrificed after 2 hours. Concentration TxS 'and 6c keto-PGP ^^, permanent metatolitů TxA ₂ and PGI ^, is determined individually for serum and plasma.

For example, compound 1,2-dihydro-3- (1-iidazolyl) -6-carbonyloxy-naphthalene (internal code of PCX 22178) at 9 mg / kg reduces serum TxB 4 concentration by up to 70% and increases the concentration of 6- keto-FO ^ up to JO%. The same compound at a dose of 100 mg / kg reduces the serum TxS ₂ concentration by 90%

Γ

and doubles the concentration of 6-ke to-PGF-v-plasma.

In most tissues, the major products of mstaboliss-U are arachidic acid PGL. and TxA ' ₂ 'a; is the jieh-ratio * plays-the main role you're '' Vaskúíárni haemoštasi. .PGI'm'protiagregation and

i. 5 time from the time the t f i 'yet'; cd 7 Tx AT - it is for aggregatorial (or, aggregate and your secretion compound) .7 FGI ₂ synthetase enzyme is mainly found in endothelial cell and produces

- -i r s- '- *,.

'* PGI ₂ 7 which prevents platelet adhesion to the arterial wall and ignites. thrombus ^; α-has vasodilating activity. - In contrast, Tama-synthetase enzyme TxA ⁴ is hlavně_ • ^v: platelets and produces TxA ^, which blocks the formation of platelet aggregates bleeding and contraction of blood vessels. As a result of opposite activities, vascular bleeding is controlled.

The compounds of the invention which are capable of inhibiting selectively TxA ₂ formation can be used as vasodilator and anti-aggregation agents. Agents, for example, in all cases of thrombosis, peripheral vasculopathy and coronary artery disease. Inhibition of TxA ₂ production actually decreases the likelihood of thrombus formation and vascular contraction with subsequent ischemic events and retains (or increases) production. PGI ₂ - improving dilataee c7, supplying blood to the tissue and protecting the vessel walls.

Another use of the compounds of the invention is in the treatment of migraine, as is known, for example, in the case of migraine, diffuse vascular contraction, which is caused by overproduction of TxA ₂ in platelets. Pathol (1971) 24, 250;

J. Hoadache (1977) II.

The overproduction of TxA4 and fcDA (malondialdehyde) in diabetes mellitus has been shown and correlated with microcirculatory defects occurring in disease etabolism (1979) 28, 394; Eu. J. Clin. Invest. (1979) £ 223; Thrombosis Haemost. (1979), 42, S. J. Lab. Clin. Ice. (1981) £ 1,

87 /. '

Thus, the compounds of the invention may be used, for example, in the treatment of diabetic microangiopathy. use as anti-inflammatory agents. As is known, it transforms

- 29 r

For example, the fluid contained in the granuloma induced by karsgen. arachidory acid in TxAg in vitro and levels of TxiU increase in the aynovial fluid of rheumatoid arthritic patients and in the fluid of inflammation induced in rats, carrageenan, prostaglandiniris (1 $ 77), and 1-7; VScand . J. Riheus. (1977) * 6, 15ΧΛ Recently '! was also prokázánopp that overproduction ŤxAg ^ _λ is reflected at pátogene2i: hypertension and that can be-used

- a specific inhibitor of the production of TxA ₂ to such a factor when _; hypertension removed SPE. J. Pharmacol. The compounds of the invention can indeed be used as hypersensives. For example, one of the compounds of the invention, FCE 22176, was administered orally to nine male SHfi rats for seven weeks at a dose of 9 mg / kg. The mean systemic pressure was controlled at 8-channel

Beckman polygrefu via a Statham pressure transducer (transducer) 7 connected to the FE catheter inserted 24 hours before monitoring I 7 'into the left carotid artery · In this model compounds per diminished W ⁵ * development of hypertension, as is apparent from Table 1 above. '*

Table 1

Healing (weeks) Mean systemic pressure Checks Treated  mm Hg E.S. mm rfg - i ..  7 177-5.06. 154.6 - 14.1

Furthermore tulle proven _ΤχΑ Ύ effect on the pathogenesis of ulcerative disorders of the stomach in relation to their considerable gastric vasokenstrikčními effects, so that even in this field it is preferred to use an inhibitor of TxA ₂ ^ íature (1961) 292, 472 /. Indeed, the compounds of the invention are indicated by "p". treating peptic ulcers. The compounds of the invention may also be anti-tumor agents. For example, it is known that selective inhibition of TxA ₂ synthesis has been demonstrated to reduce lung metastasis and slow tumor growth (19S2).

1S§7.

/ due to the correlation between TxA synthesis 'and transport ^r <... transport.'. Calcium has recently been shown by some authors, specific inhibitors of Txa synthetase, such as the compounds of the invention, can also be used as an osteoporosis agent, e.g. pancreatic, osteoporosis TTrostaglandins, (1981) 21; 401 / ·. _; In addition, compounds of the present invention are indicated for the treatment of angina in this direction, for example, it is known that high levels of Ixa are present.

- are found in patients with Frinzmetal angina ^ rostaglandins. and Led. (1979) 2, 24} and in patients with recurrent angina attacks / jixth Intern. Cocgress on Thromboais

Lonte Carló, October 1980, Abs No. 140 /.

The felted anti-aggregation activity of the compounds of the invention was evaluated in vitro and in vivo, e.g. le modified methods of Borna ZSorn G.V.R., Nature 194. 92? (196-21 / a Silvera ZSilver S5.J., Science 183. 1085 (1974) 2).

The compounds of the present invention were found to have in vitro inhibitory activity to platelet aggregation induced by collagen ' ^J some' ADP '(α'ednosine-5 * -difdsphate) ”in platelet-rich guinea pig plasma ^ unkin Hantley Iva: PDH (SPF) Ivanovas GmbH, Germany / · for example, the compound 1,2-di ^-; Hydroxy-3- (T-imidol) -6-methoxy-naphthalene (internal; Cod ^. Compound PCE 22.466) was found to be active on both ADP and collagen-induced platelet aggregation: at 25 mcg / ml completely inhibits collagen-induced platelet aggregation in three of the four platelet-rich plasma samples.

The compounds of this invention are more potent inhibitors of platelet aggregation induced in vitro, e.g. collagen than the compounds previously disclosed in U.S. Patent 4,342,775 and U.K. Published Patent Application 2'ΊΟ6,509 A.

Results obtained, for example, by testing the compound of the invention FCE 22456 and the known compounds of G- (1-imidazclyl) 2,3-dihydro-6-chloro-4H-1-benzopyran-4-one (internal code compound FCS 20204), which is described in US 4,342,775, and 2- (1-imidazolyl) -3,4-dihydro-7-methoxy-1 (2H) -naphthenone (internal code compound FCS 21848), which is described in UX published patent application 2,106,509 A, are given in Table 2.

- 30 ft

Table 2

Compound In vitro, concentration mcg / ml - - - F-:-:- % ir.hibice ..FCL; 22466. ? 'FCr 20204 ^' FCE.2134S . t, iSF '·; - < ^y - ^? 12.50. . · 13,50- ... ' -7 / -50 --- Λ in

FCE 22178 is also suspended in ethocel ^and administered orally to rabbits (New Zealand, white) at a dose; 2 mg / kg one hour prior to arachidonic acid injection at 1.4. mg / kg.

The test compound greatly reduces erachidono-VQu acid mortality (Table 3): ----- Table 3

Fodáno Dose, mg / kg / pers ... Mortality · ůíethccel ^ 9/9 Compound FCE 22178  2 3/9

? Ě ';; “'”: T ^ fctabulce ^ 3 · - effect is given. FCS compounds.

arachidonic acid-induced mortality of rabbits (1.4% &lt; kg / kg). .

. As constant above, certain compounds of the present invention do not show more specifically those compounds wherein one of the substituents 2, K 2, R 3 and R 3 is scurine.

TO

I ^C ~ AII ^C0 ^ ^{9 QStatn:} Sutstituenty ^d have the meaning as indicated in Kžorci X no activity on the system TxA ^ / ^ RGI but eat surprisingly high activity to reduce cholesterol .a triglycerides by reducing the total cholesterol HLL sé ... ^'ru> - as well as increasing the ratio of total cholesterol \ -lipoproteíň -and-' A-lipoprctein. As is known, drugs having such. the effects are useful in the prevention and therapy of etherosclerosis; . '

Glueck CJ, Artery, 2, 195 (1976); _Dey ** wxJ.

** - * # · ke (Ed.) Annual Reoorts.in Cedicinol Chemistry, 1J, 164, '? * Chapter '2 -: · · ·.

The -C-C-COR substituent in the compounds of the above.

, _r ..... '^ r · phenomenon · ·. - ”· -ir- * c« '* · *''. · **. v - ·.

<... knows'. ': ~ <Λ' ··, -'- ·. '· - · · _κ . Λ ... ·· -. ',. . '·· “- · ..... * ··. - '.. i ..., ...;' · '·. · Í £ j. ^ R · Ί -vw 7 'Σ. ^' Γι 'V' ^{the first} '* .Ύ "<. - - · -. ' * .. · 1 ·>'. 1 · '. '· Í * ^λ *. .

U.S. Patent No. 4; 342/775 with U.H. However, such known compounds still have the ability to reduce lipid levels and therefore have anti-atherosclerotic activity. Therefore, by introducing this new substituent into the bicyclic compounds, these activities have unexpectedly intensified. The effect of this particular class of compounds of the invention and the compounds of the aforementioned U.S. Pat. and U.K. of the published patent application was evaluated on CER (SPF Caw) groups of male rats fed a six-day hypercholesterolaem diet according to the C.E. Day / Schurr. P.E., Schultz H.R., Day C.E. (Eds) Atherosclero3Is and, Drug Discovery - Flenum Puh Corp., 217 (19761 / (experiment δ. 1), or fed Startharthi etou / Altromine Z (experiment No. 2). Atromine ”is The compounds are suspended in Methocel (methyleeluloza, 0.5% duke suspension) and administered by gavage for 4 days.

... Groups of control animals are treated only with a suspending agent.

Total serum cholesterol * ee was determined by the method of Trinder P.J. ^ T. Clin. Pathol., 22, 24.6 (1965).

Triglycerides contained in serum are. determined by Mendez J. Clin. Chem., 21, 766 (1575-7).

Total HEL serum cholesterol is determined according to Eemacker ^ P.N.fc. / Clin. Chem., 2J, 1238 (19771).

Statistical analysis in Experiment 1 is performed by Student. independent sample test or the Cochrane test when the changes are not homogeneous at the F ratio of the αliss C.l. Statistics in Biology, Vol. 1, page 213- Kc Graw Hill Eook Company-, New York, -1967; Cochron W.G., Cox G.L. - Experimental designs.- J. Wilsy's Sons Inc., New York, II, ed. (1966) page. 100 / ..

-: ///: 33 -. Pro ^- experiment δ.-2 was used the following statistical methods: · Analysis of changes Bartlstův test / Properties of svďficiency and'Statistical Tests - Why. the Hoyal Scc. of London ' 160 (1937) pages 266-262] to determine the homogeneity of the changes and Dunnett &apos; CW. - J. Ammer. ŠtavOssi. 50 10967 (1955) U Λ / animals treated ~ ^'SI: handing ^{hyperchóle_3terolaemhí:} diet were tested in' accordance with this invention the compounds found to reduce total cholesterol and increase v.séru total serum HDL. cholesterol in a highly prominent manner, whereas the compounds of the prior art exhibit only mild effects at the same dosage levels.

Table 4 shows the results obtained, for example by testing the compound of the invention 1,2-dihydro-3-β-imidazolyl) -6- (2-carboxy-isopropoxy) naphthalene (internal code: FCS 22473) and known PCE compounds. 2O2C4.

'Table 4 (experiment δ. 1)

Served Dose mg / kg / pers Total serum cholesterol % of changes against controls Serum. HDL choles-. terol% changes against controls · _? ·, Registration number ““ 22473 ”’ - ₂₇ ...... ·. -73 +77 / ...... FC 20204: '/./ 2 ₅ ··  . +7 +49

In animals fed a standard altromine diet, the test compounds of the present invention are found to reduce both total serum cholesterol and serum triglycerides, whereas the prior art compounds are found to be less potent and exhibit the same effects only in those cases when administered in larger doses. ·. The following results are shown in Table 5, e.g., by testing the compound of the invention with PCE. 22473 and the known compounds FCE 21646.

Table? (Experiment # 2)

Filed · ''; Dose ^{; 1} Total serum cholesterol Serum HDL chole- sterol sterol . _____ mg / kg / pers changes against % -when against con- . ,. ' .lam trolém .5? OBJECTIVE ^: 22473> · 67έ? 67 / ΐ ^? - /. - ^T , -32 - · - </ · ” OF'' ρο ¥ '”· 2ί'έ'Δχ · ί * ;. ·· * ‘. sb · i τ - 50,00-  ineffective .. - ^: '' / · Ineffective

Due to their increased activity decrease obsah.lipidů. · There is a -Effects on HDL ^row. cholesterol can be. the compounds according to the invention, in which one of the substituents is

R 1 and R 3 are the radicals R ⁴ -41.

........-.......... τ ........- O-C-COR- -a, other substituents. have ________.

R meanings given in the preceding formula I, 'used in therapy -......

treating dislipidsewia and atherosclerosis.

A dosage level that is suitable for oral administration to adult humans' moving-in-eloučen invpodle present invention, 'nápřr'ul'72-dihydro ^<3 ro-3- (l-imidazolyl') "O-karboyy-naphthalene, '· - -—. in the range of about '5 mg to about 500 mg per dose 1 to 3 times daily. ", preferably from about 20 mg to about 150 ung for dose 1 to 3 times ~ front ~ which ~ z" EVIS ^- Na @ hěmbcl ^- a' age ^- as ^_ well ^- i-HMO tNOS that price ch-- patients.

Toxicity; The compounds of the invention are negligible so that they can be safely used in therapy.

lysis and rats, which was not administered nine hours food ^J * were treated orally with single administration of increased doses and maintained on normal chow. The indicative acute toxicity (LD_ ~) is estimated on the seventh day after administration and found to be ^: greater than 3000 mg / kg,.

On the other hand, the value of DD-1 is some of the known compounds having a similar chemical structure, for example 1,2-dihydro-3-yl-imidazolyl-ethyl) naphthalene and 1,2-dihydro-3- (limidazolylmethyl) -benzene. The V-methoxyno-naphthalene described in Japanese Patent Application Publication No. 156435/1979 (61566/1981), which are very active inhibitors of TxA 2 synthesis, has been found to be less than 200 mg / kg / axis when estimated in mice according to the same procedure.

The compounds of the invention may be administered in a variety of dosage forms, for example, by oral administration in the form of tablets, capsules, sugar or tablets coated with filaism, liquid solutions or sealants. in the form of suppositories, parenterally (e.g., intra-muscular vein) of the hedgehog, or infusions. /

In the present invention, the intravascular administration is also preferred. Exactly: the dosage "depends" on the patient's illness, age, weight and condition and the route of administration.

The invention encompasses pharmaceutical compositions which comprise a compound of the invention in association with a pharmaceutically acceptable excipient which may be a carrier or diluent.

The pharmaceutical compositions containing the compounds of the invention are usually prepared according to conventional methods and administered in a pharmaceutically acceptable form.

The solid oral forms may contain, for example, together with the active compound diluents, e.g. lactose, dextrosis, sucrose, cellulose, corn starch or potato starch; lubricants such as silica, talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycols;

..binding, eg. starches, arabic. klovatinu ,. gelatin, "methyl".

cellulose, &quot; carboxymethylcellulose, or polyvinylpyrrolidone; disaggregating agents such as starch, alginic acid, alginates or sodium starch glycoletes; swelling mixtures; tarviva; sweeteners; wetting agents such as lecithin, polysortates, lauryl sulfates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Said pharmaceutical preparations "may be prepared by methods known per se, for example by means of mixing, granulating, tabletting, sugar coating" or film coating.

Liquid dispersions for oral administration may be, for example, syrups, emulsions and suspensions. The syrups may contain as carrier, for example, sucrose or sucrose with glycerin and / or mannitol and / or sorbitol; in particular, the syrup to be administered to diabetic patients may contain as carriers only those products which do not metabolize to glucose or which are metabo-

lyses in very small amounts to glucose, for example sorbitol.

; The suspensions and emulsions may contain a carrier, for example. {· '.

(natural resins, agar, sodium alginate, pectin, cetylcellulose, corbexyraethylcellulose, or polyvinyl alcoholconol. Suspensions or solutions for intramuscular injections may contain a pharmaceutically active compound, in a liver carrier, as:

r.apř. sterile water, olive oil, ethyl oleate, glycols, eg propylene glycol, and, if required, appropriate quantities of hydrogen, chloride, lidocaine, ........>. .. <

·. ;;; Solutions for intravenous injection or infusion may contain as carrier, for example, sterile water neto, and may preferably be in the form of sterile, aqueous, isotonic saline solutions. ....._ ..

Suppositories may contain, together with the active compound, pharmaceutically acceptable. a carrier such as cocoa butter, polyethylene glycol, a polyoxyethylene sorbent surfactant ester. _; and fatty acids, or lecithin. __ _

The infrared (IR) spectrum of the compounds is measured in solid phase (KHr) or in a solution of Hujol or in a solution of a suitable solvent, such as CHCl 3, using a Perkin-yellow spectrophotometer.

125 * Nujol is a registered trademark.

...... The nuclear magnetic resonance spectrum (NIViR) is measured. .. · _: -.

preferably in a solution of dimethylsulfoxide-dg or CLCl 2 using a rruker HFX 90 fo-hertz.

The R ^ values are determined by thin layer chromatography (TLC), on easy-to-use silica gel plates with a coating thickness of 0.25 mm. .........

The following examples illustrate the invention in more detail, but without limiting it.

Example 1

A solution of 3- (1-imidazolyl) -2,3-dihydro-6-chloro-4H-1-benzopyran-4-ol (5.4 g), acetic acid (61 mL) and sulfuric acid (27 mL) was heated at 50 ° C for 6 hours. After pouring the solution into the bath water. (20 mL), neutralized with NH 4 OH, extracted with CH 2 Cl 2, dried and evaporated to dryness.

-Ϊ1> 3.9 £ ζίSká third-IL-Í3ii - S2olyl) -6-chloro-L-2'rí tenzopyr £ _nu> mp 116-120 ^C (isoprcpylalkohol) -.

Elemental analysis:

.dated: C βΙ, βί ^ .Η 3.93; K11, S9; Cl, 15.35. Calculated: for ^G, 61.94; H, 3.90; N, 12.04; Cl 15.24 • TLC / eluanVCK Cl ^ RCH? OH (170: 30); '· - \' ^f = ^Cy56''3: / 7!

Nk-R (CDCl 3 -) Tpnu 5.11 (2'H, d, -O-CHg)

6.49 (1H, δ s, -O-CH ₂ -C = CH-)

6.54-7.76 (6H, m, aromatics + imidazole).

The following compounds are prepared analogously:

2-methyl-3- (1-imidazolyl) -6-carboxy-2H-1-tenzopyran, m.p. 216-220 ° C and 225-227 ° C (depending on crystallization form), elemental analysis: ·· .. ···

Found: C, 65.20; H, 4.75; N, 10.54.

Theoretically for ^{G H} i4 i2 ^ 2 ° ^{3: C,} 65.61; H, 4.72; N, 10.93 NKR (BkSC-d6) .ppm: 1.36 (3K, d, --C1 -).

-5, 76 (1H, q, -O-CH-)

6.95 (1H, s, -O-CH-C = CH-) 6.29 (1H, br s, -N-CH = N-)

IR (KBr): (CO-H) carboxylic acid 30OC-2300 cm -1. ——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————

3- (1-imidazolyl) -6-methoxy-2H-1-benzopyran, m.p. 104-106 ° C, elemental analysis:

Found: C, 66.20; H, 5.33; N, 12.24

Calculated for H ₁₂ N ₂ O _2: C, 66.40; H, 5.30; N, 12.27. TLC. eluant CK CL · _0: CH.OH (160: 20) ⁷ 2 cj.

Rf = 0.4

MS (CDCl 3) δ Tppm: 3.77 (jK, s, -C-CH 2)

5.00 (2H, d, -O-CH3 -)

6.45 (1H, S, _-CH? -CH = CH-)

6.61-7.74 (6H, m, aromatics + imidazole),

3-β-imidasolyl) -6-carboxy-2H-1-benzopyran ^; tt> 2 ° C _Ă elementary analysis:

Found: C 64.1; H, 4.12; N, 11.59.

Calcd. For C 64.45: t 4.16; N, 11.56

- 38 TLC eluant CK-Cl, CH.GH: CH ₀ CCQH (160: 40: 5) ^} 2. j J i -0.4.

K 2 R (ESO 2 -dg) Λppm: 5.32 (2H; s; -G-CH 2 -); δ 6, C 6,1 C 17 H, m, aromatics + _d imidasol + ^s ; • -Οίν- ΟΚ ^ -). · '- ¹ Ji.?','· J.; ^f ?, ... · '

-. . _K '·· ¹ ~ k · _ν - t ·

2- (3,4-dimethoxyphenyl) -3- (1-imi Sasolyl) "5 = THC: y ^j = 2H" = l _benzopyran; * ·. :

. Elemental.analysis:; .

.Found: .C 59.00; H, 5.49; N 7, 6. .

7yp t x teno for Č2 ^ ίζθΝ ^ O: Č ^_ 6'9,2 2? H ''. 553Ν '' 7 6g

TLC / CH 2 OH: CH 2 OH (180: 20) ....................

R f = 0.32 ms: m / e 364 (Ϊ +, 100%); 349 (M-15, 20%); 296 (^ - 68.17%)

281 (296-15, 23%); 68 (91%) ........

3- (1-imidazolyl) -6- (2-carboxyisopropoxy) -2H-1-benzopyran 3- (1-imidazolyl) -6- (2-carboxyvinyl) -2E-1-benzopyran,

2-methyl-3- (1-imidazolyl) -2H-1-benzopyran,

2-Methyl-3- (1-imidazolyl) -6-hydroxy-2H-1-benzopyran, 2-methyl-3- (1-imidazolyl) -6-methoxy-2K-1-benzo pyr an;

2-methyl-3- (1-imidazolyl) -7-carboxy-2H-1-benzopyran,

2-methyl-3- (1-imidazolyl) -4-cartamoyl-2H-1-benzopyran,

2-methyl-3- (1-imidazolyl) -6- (2-carboxyvinyl) -2H-1-benzopyran, 2-methyl-3- (1-imidazolyl) -6- (2-carboxyisopropoxy) -2H-1-benzopyran,

2-Methyl-3- (1-imidazolyl) -5-hydroxy-7-tert-butyl-2H-III. .

ténzopyráh,

2-Isopropyl-3-l-imidazolyl) -6-carbonyl-2H-1-benzopyran, 2-isopropyl-3- (1-imidazolyl) -6-methoxy-2H-1-tenzopyran 2-cyclopropyl-3- (1-imidazolyl) -6-carboxy-2H-1-tenzopyran, 2- (3,4-dihydroxyphenyl) -3- (1-imidazolyl) -6-hydroxy-2H-1-benzopyran, - *

2- (3-pyridyl) -3-β-inazazolyl) -6-carboy-2H-1-tenzopyrrine,

3 '(1-imidazolyl) -6-hydroxy-2H-1-benzopyran, 2-methyl-3- (1-iimidazolyl) -6-ethoxycarbonyl-1H-1-thiopyran,

2- (4-Hydroxyphenyl) -5,7-dihydroxy-2H-1-tenzopyran a

2- (3-pyridyl) -3- (1-imidazolyl) -6-methyl-2H-1-benzopyran.

- $ 3 Top used 3- (1-imidozely1) -2

3-Dihydro-5-chloro-4H-1-thenzooyran is prepared as follows:

NaEH 4 (1 g) was added portionwise to a solution of 3-β-imidazolyl) -2,3-dihydro-6,6-chloro-4H-1-tenzopyran-4-one (2.7 g) in ( 70-100) at; ^5-and-0 lč. C4oměs · a; The mixture is stirred at room temperature for one hour, treated with water (100 ml), extracted with CHCl3. vyXfceOH. - Those two dry. 3 to dryness to give 3- (imidazolazolyl) -2,3-dihydro-6-chloro-4H-1-thiazopyran-4-ol. (2.7 g).

.Elementary analysis: '

Found; C 56.76; H, 4.44; N, 10.86; Cl, 13.65

Calcd. C, 57.48; H, 4.42; N, 11.17;

Cl, 14.14

ΝϊδΛ '(pyridine-dj) <Tppm: 4.25-5.00 (3H / m, -CCH ₂ -CH-N <)

5.18 (1H, d, H-CH-)

6.96-8.12 (6H, m, aromatics + imidazole)

The above 3- (1-imidazolyl) -2,3-dihydro-6-chloro-4FE-hensopyran-4-one is prepared as follows:

A solution of 2-hydroxy-5-chloro-N - (1-ircidezolyl) acetophenone (2.4 g), pareformaldehyde (0.3 g) and acetic acid (45 mL) was refluxed for 30 minutes. The solvent was removed under reduced pressure, ethanol was added and the impurity was filtered off. The solvent was evaporated and 2 g of 3- (1-imidazolyl) -2,3 * dihydro-6-chloro-4K-benzopyran-4-one was obtained as a residue, m.p. 123-125 ° C (i.sCH / H 2 O),

NIR (CDCl3) cTppm: 4.5-5.1 (2K, · m, '- O-C ^-CH <)

5.84 C1H, m ,. -O-CHg-CH)

6.92-7.84 (6H, m, aromatics + imidazole).

The above 2-hydroxy-5-chloro-N- (1-iridazolyl) acetophenone is prepared as follows:

A solution of 2-hydroxy-5-chloro-1-bromo-acetophenone (7 g), imidazole / (6 g) with N, N-dimethylformamide (50 ml) was heated at 4.0 ° 0 for 2 hours. The solution was poured into ice water and the solid was filtered off to give 6. g -2-2-hydroxy-5-chloro-1- (1-imidazolyl) acetophenone, mp 201-203 ° C (ethanol).

• ^ -40-

Example 2

7.6 g of 1,2,3,4-tetrahydro-2- (1'-imidazolyl) -7-carboxy-1-naphthalenol were treated with glacial acetic acid (60 ml) to give 7.6 g. Sulfuric acid (10 µl) was added and the mixture was heated at 100 ° C for 4 hours. . ?

and·. The reaction mixture was poured into ice-water (100 ml) and the pH adjusted to neutral by the addition of 35% NaOH. The precipitate was allowed to sit, filtered and washed with water to give 6.7 g of 1,2-dihydroxy-3-allyimidazolyl-1H-box-naphthalenium. , —T.t -323 = 6 —C1-1: Elemental analysis;

Found: C, 69.32; H, 4.96; N, 11.51

Calcd for ^: 69.96; H, 5.03; N 11, .6.5 .....

TLC, eluent CHCl 3 / CH 2 OH; CH 3 COOH (45: 5: 2.5) sf = 0.45 ..... ’; ..... '’

NKR (CDCly CFCOC-D) < T. ppm: 2.6-3.4 (4H, m, --C 1 H - C 1 -) _______________ ___________________ _L ________________, _, 6, 95 .., (1H, .S s, _-C, H = C -} ______. 7.36-6.39 (7H, m, COOH + aromatics + + imicazole) 15 (KBr):> 0 = 0 1685 cm -1 ¹ ____ _: _

The following compounds were prepared in an analogous manner:

1,2-dihydro-3- (1-imidazolyl) naphthalene

Elemental analysis:.

Found: 076.3; H, 6.22; N, 13.95.

Calcd. For ^c 79.56; H, 6.16; N, 14.27

TLC, eluant CH _"Cl: CH.0S (170: 30)

t. · έ -4 .....; - - ...........................:

2f = 0.71

N k R (CDCl 3, CDCl 3): 2.6-3.1 (4H, c, -CH 2 CR--)

6.4 (1H, bs, -CH = C-)

7-7.6 (7H, m, aromatics + imicazole), 1,2-dihydro-3- (1-imidazolyl) -6-tert-butyl-7'-hydroxy-naphthalene, m.p. 241-243 ° C; . Elementary analysis:

Found: C, 75.43; H, 7.39; K 9.55

Calcd. For C 76.06; H, 7.51; N, 10.43

TLC, eluent CHCl 3 CH 3 OH (160: 20) = 0.35 ^J

- 4i

(PKSO-όχ) <f ppm: 1.34 (2H, s, tert-butyl)

- · - · 2.79 (4H, a, -CH 2 -CH 2 -)

6.70 (1H, s, --CH.dbd.C-)

6.61-6.06 (5H, a, aromatics + imldasol) 9.34 (1H, bs, -OH),

112-dihydro-3 - ( 'l-iaidáz6lyl) -7-k9rbsxy-ňaftelen--' obtained ja '' N ¹ ko hydrochloride, mp 290-295; 0, complementary analysis: '

Found: C, 60.50; H, 4.60; N, 10.05; Cl, 12.65

Calcd for C 14 H 16 ClN 4: C 60.77; H, 4.71; N, 10.10; Cl, 12.70

TLC, eluent CHCl ₃ : CH ₃ OH: CH ₃ COCH (60: 20: 5)

Hf = 0.6

NkE (DfcSO): 3.04 (4H, m, CHg-CHg). . 7.17 (1H, s, CH = 2 '>)

7.72-9.36 (6H, m, aromatics + imidazole, * ‘7)

1,2-dihydro-3- (1-imidazolyl) -6- (2-cartoxvinyl) naphthalene, 'Elemental analysis:

Found: C 72.71; H, 5.26; N, 10.65

Calcd for ^C 15 ^H 14 ^N 2 ^O 2 ^{: C} 72.18; H, 5.26; N 10.56 TLC, eluent CHCl 3 CH 3 OH (90:10)

Hf = 0.30. '.....

NER (O = SO ₆ ) <r _: ppm: 2.6-3.2 14E, n, CHg-CHp

6.45 (1H, d, C • 0 • CHCH) 6.64 Í1H, m s, CH = C-) 7.34 klH, d, 'c- 0 , p u-H u S 7,10- 6.16 Í6H, m, aromatics +

1,2-dihydro-3- (1-imidazolyl) -5-hydro-7-acetyl-naphthalene,

01/01, 135-140 ° _C?

Slenentární analýza:

Found: No 70.33; H, 5.54; 1 -:, 10.68

Calcd. For C 70.65; N, 5.55; N 11, ol

TLC, eluent CECl -: CH.OH (160: 20)

Jf = 0.6

<CDC1. (ppm): 2.60 (3H, s, CH.) B, CS.-CH-) r - ’2.53 s 4 ^T s, (1H, s, CH-C-) • 6,70- 7.69 (5H, m, aromatics ., - - - l - ´ * · -. , · 4 1 2 i “J .. ...... · /;..·. J-t, j j  (lKj , W, OK),

1- (2-dihydro-3-yl-phenyl-3-yl) -7-oxo-naphthalene

Elemental.analysis: ./

Found: C, 75.51; H, 5.07; N, 16.69

Calcd. For C 76.01; H, 4.56; and! 19.00

TLC: (CHCl3): CH2 (OH, CCCl: 1.0.0):

Rf = 0.45

IR (KBrj C = 22 2220 cm ” ¹ , ........ ..........

1,2-dihydro-3- (1'-idazolyl) -7-fluorinaphthalene;

Found: C, 56.55; H, 3.95; N, 10.16; Br, 26.52

Calcd _. C. 56.73; H 4 OC .; _T M 10., 16 j-Br. 29,1.0 'TLC i "elu" CHCl 7: CH 3 OH' (90: '10) '"^> ^ ^{T i} ' ^r ~ '

Rf = 0.5

MOR (CDCl-1. <^ Ppm: 2.6-3.2 (4H, m, CH3 -CH3)) ^: """6.45, 1H, §.a, CH = C -)" ^ ^: 6.11-7.60 (7H, m, aromatic imidazole)

1,2-dihydro-3-C1-isidazolyl) -6-methoxynaphthalene, m.p. 63-65 °

Elementary analysis:

Found 73.96; H, 5.11; N, 12.30

Calcd for ΟΟΗ, ^Ο: C 74.31; H, 6.23; N, 22.36

TLC, eluent CHCl 3: CH 3 OH (190: 10) δ

Rf = 0.7

NiviH (CDCl @). ÍTppm: Í4H 2.56 to 3.05, m, -CH ₂ -CH ₂ -). 3.72 C3H, s, -OCH3

-. 6.41 (1 H, dd, -CH = C-)

6.62-7.76 (6H, m, aromatics + imidazole),

1,2-dihydro-3H-imidazolyl) -5-tri-6-methoxynaphthalene, mp 140-144 ° C _;

Elemental analysis: '

Found: C, 54.76; H, 4.25; N, 9.09; Er 26.02

6,84-8,18- (5H, m, aromatics + imidazole), 1,2-dihydro-3- (1-imidazolyl) -7-aethoxynaphthalene, m.p. .1. 1CS-11C ° C * '-Elementary analysis:

Found: C 73.09; H, 6.09; N 12, 19-.

Calcd for C 14 H 14 O: C 74.31; H, 6.23; M 12.38

TLC, eluent CHCl 3: CH 3 OH (195: 5)

RF = 0.3

3.78 (3H, a, OCKp 6.47 1H, s, CK-C-N)

6.70-7.80 (6H, m, aromatics + imidazole)

1,2-dihydro-3- (1-imidazolyl) -8-methoxynaphthalene

1,2-dihydro-3- (1-imidazolyl) -6-hydroxymethylnaphthalene

1,2-dihydro-3-yl-imidazolyl) -5-carboyynaphthalene,

JI í

1,2-dihydro-3- (1'-imidazolyl) -6-methoxy-7-thromnaphthalene ^; '·

1,2-dihydro-3- (1-imidazolyl) -6- (-2-ethoxycarbonyl vinyl) naphthalene,

1,2-dihydro-3- (1-imidazolyl) -5-carbaaoylnephthalene,

1,2-dihydr 0-3- (1-imidazolyl) -6-hydroxy-7-carboxynaphthalene,

1,2-dihydroc-3 (11-imidazolyl) -6-carboxymethylnaphthalene,

1,2-dihydro-3- (1-iidazolyl) -S-carboxynaphthalene,

2- (1-Imidasol-5-carboxyxyindene) a

2- (1-imidazolyl) -5-ethoxyindene.

The above 1,2,3,4-tetrahydro-2- (1-imidazolyl) -7-carboxy-1-naphthalenol was prepared by reducing 8 g of 2- (1-imidazolyl) -3,4-dihydro-7-carboxy-1- (-2-H) -naphthalenone with NaBH, (3.6 g) in -methanol (2CC mL). The reaction mixture was stirred at room temperature for 4 hours and then 200 mL of water was added. The organic solvent was evaporated under vacuum and HCl was added to the residue until pH 6. The precipitate was filtered off and washed with ethyl acetate. is obtained. 7.8 g of product, m.p. 175 ° C.

4 = -4 • L Λ <4 * / ynumber for

NI.1 (TKSC-aJ)

... -r ~ · ^ o

Elemental analysis: .

Found: -C 64.51; H, 5.30; II 10.81 ^C 14 ^H 14 ^N 2 ^C 3 ^{: C 65} '^{1C; H 5 &} gt ^{; 46; N 10} > ⁸⁴ ......

target ^ ppn: -. 2.14. (2H, m, ’C ^ -CH ^ -CH-).

^? : 2.97 (2H, m, C 1 H -CH 2 -CH-) /

4.23 (1Kf dt, -CH-N-). 4,7S- (1H, <3, —CH — OH) _t

6.10 (2H, bs, OH + COCl 3) ^: 6.9-8.2 (6H, m, aromatics + imidazole).

, g - (-) - (-) - = - (- (imidazolyl) -3,4-dihydro-7-carboxy);

--—-— l - {- 2-H -) - naphthalerion - is being prepared._resultingly: __

11.2 g of 2-thromo-3,4-dihydro-7-carboxy-1- (2H) -naphthalenone are dissolved in DIiF (50 ml) and added dropwise at room temperature to a solution of imidazole (14 g) in DMF ( 70 ml) *

The mixture was stirred; at room temperature for 10 hours and then, the organic solvent is evaporated under vacuum.

—T ₀₂ pug-v = ethanol (100 ml). Addition of diethyl ether and filtration yields 8 g of 2- (1-imidazolyl) -3,4-dihydro-7-carboxy-1- (2H) naphthalenone, mp > 290 ° C, m.p. .

^- $ -CKBr -I -) - yC = 0 L-700-cm ~ -------

.. Nkti (CF-jCOCD) ζΛρρη: 2.92 (2t, m, C 1 -C 6 -CH-)

3.52 (2H, m, CH ₂ -C ^H 2 -CH-).

5.67 (1H, dd, --CH--)

7.57-6.63 (6H, m, ... chasuble + · imidazole)

TLC, CH-COCKyH-O / Ci-kCOOH (90: 10: 5) ant. J 3 2 3

..... Rf- = -.0.45 -.........-..... ·; ............. ...... ..........

The above 2-bromo-3,4-dihydro-7-kcřbo '- l- (2 i) -naphthalenone was prepared by reacting the known ^3,4-d dih5 ^{dihydro-7-kai'} carboxy-l (2H) -naphthalenone (8 g) with CuBr ?. (18.76 g) Y. ethyl acetate (400 mL)

The suspension was refluxed for 5 hours, then cooled and filtered. The solid was washed with ethyl acetate, the combined organic layers were washed with water, dried over anhydrous Na 2 SO 4 _. SO 4 and evaporated under vacuum to give 8 g of product, mp 185 ° C.

Elementary analysis:

Found: C, 49.15; H, 3.25; Br 29.51 '............

Calcd for C 24 H 25 BrO 4: C 49.10; H, 3.37; Br. 29.59

- 45 Ni .: iC ?, COCL. _; ) «Γρρη.

2.5 (2H, m, -Olu 4 -OH-) · 3.2 (2H), m. -CH.-CiL-CH- 4.95. (1H, CD, -CH-)

7.53-3.65 (3.H, ..m, .aromatics) ’, * '’ · _' -... ’...’ · ‘

Example 3

A solution of 1,2,3,4-tetrahydro-2 H- imidazolyl) -7-methyl-1-naphthylenol (5 g) and concentrated hydrobromic acid. (140 mL) was heated at reflux for 8 hours.

The solution was poured into ice water and the pH was adjusted to alkaline by the addition of NegCOy. The solid precipitate was filtered off, washed with water and dried.

The crude product is purified by washing on silica gel using CHCl 3 / CH 2 CH 2 Cl 2: 20 to give 4.5 g of 1S-dihydro-O-d-imidazoles-D-hydroxynaphthalene,

m.p. Mp 218-220 ° C. y

Elementary analysis:

Found: C 72.55; H, 5.65; N 13, C4 \

Calculated for 0 _{13 Η} χ2 Ν ₂ 0: C, 73.56; H, 5.7; N, 13.19

TLC, eluent CHCl 3 / CH 2 OH 180-12 Rf = 0.28.

IUR (DkSO-d₆) CTPP: 2.82 (4H, m, -CH ₂ -CH ₉ -) _t. 6.54-8.13 (6H, m, aromatics + imidazole)

6.61 (1H, br s, -CH = C-). 1C (KBr): .msx, cm -1. ,. 3440 (OH phenol)

2690 8.2610 (additional NH ⁺ )

1645 (additional C = C).

Analogous-procedure following compounds were prepared: 3- (l-imidazolyl) -2H-tenzopyran, mp 50-52 ° C _Z ·· • Elemental analysis:

Found: C, 71.98; H, 5.03; N, 14.01

Calcd. For C 72.71; H, 5.08; N, 14.13

TLC, eluent. CH ₂ Cl ₂ : CK ₃ OH (180: 20) ·

Rf = 0.5 cm @ -1 (CDCl3) ppm; -5.04 (2H, d, -O-CH2) - 6.50 (1H, 5 s, -CH ₂ -C) = CII-).

• 6.80-7.70 (? H, a, aromatics + ~ imidazole),

-. . 1,2-dihydro-3- (l-ipudazolyl) -6-karboxynaftal9n, ·· .- '</ · --1.2-dihj ^of dr o-3- (l' iaida20lyí) -7karboxynáftalan l / 2-dinyldb-3- (1,1-imidazolyl) -5-carboxynaphthalene, 1- ₍ 2-dihydro-3- (1-imidazolyl) -8-carboxynaphthylene, and

1,2-dihydro-3- (1-imidazolyl) -6-tert-butyl-7-hydroxynaphthalene. Above used 1,2,3,4-tetrahedro-2- (1-imidazolyl) -7 ——-- Εΐ ~ βΐΗοχ7- ± -η & &5Ε01 ^ 3 ' 4-Methoxy-2- (1-thiazolyl) -7-methoxy-1- (2H) -naphthalenone using Na 3 H 4, following the same method as described in Example 2 for 7 cartoxy derivative, 1.1.159-162. Deň: 32 ° C. Elemental analysis:.

Found: C 66.55; H, 6.84; N’11,40 *

Calcd for C 19 H 18 N 3 O 4: C 68.63; R 6.6; N, 11.46

-------- TLCreluant-CHCl 3 (GH 4 H-deO: 20) -----------—

3I = 0.3? N R (CDCl 3) T Tppm: 1.95-2.70 (2H, m, -GH 8 -CH 2 -CH-).

- - - - - 2791 - (- 2H - m - GK - ₂ - GH - ₂ - GH -) ·, -, 3., 79 (3'H, s, OCKp; 3.86-4.40 (13, m, -CH-N-) 6.20 (1H, bs, OH)

6.64-7.50 (6H, m, aromatics + imidezole). The above 3,4-dihydro-2- (1-imidazolyl) -7-methoxy-1- (2H) -naphthalenone is prepared from 3,4-dihydro-2-bromo-7-methoryl-1-carboxylic acid. (2H) -naphthalenor and imidazole according to the same procedure as described in Example 2, mp 115-116 [deg.] C.

Elementary analysis:

Found: C, 69.44; H, 5.82; N 11,5? Calculated for. * 9 »40; H

ΪΙΟ, CHCl 3: CH 2 OH (160: 20) ·

Rf = 0.55

NiLi (GKCl3) <f ppm: 2.42, 42-2, 72 (2H, m, 3.02-3.35 (2K, m)

5.82; N 11.56 ch ₂ -ch ₂ -gh- ch ₂ -ch ₂ -ch-)

- ... ' -47 '3.24 Í3H, s, 1 4.96 Í1H, dd, 6.961700 cm 7,55 -1. » ¹ (6H

'-'Shora used ·· ·, .3'Í4Tdihydro "2 trcm methoyy-7-L-s 2H) ^{-naftfilenór?':} Providing ^an *; brozací 'friend / 3,4-dihydro-7- £ Ethyl tert-1 (2H) -haftelenone with copper (I) bromide (CuRr), following the same procedure as described in Example 2, mp 73-SO x,

TLC, eluent CHCl 3 / CH 2 OH (170: 30) R f = 0.55 ^J

Kur (CDCl: 2.45 (23, m, _-CH? -CH ₂ -CH-), 2.95. (2H, her -ΟΚ -Οί ^ ^ -ΟΗ-) 3.75 (3H, s, - OCH ₃ ) ''

4,66- (1H, ^DD, -CH-) "

6.91-7.49 (3H, m, aromatics).

Example 4 ν; ^! · Χ

A solution of 3- (1-imidazolyl) -2,3-dihydro-6-methoxy-4H-1-benzopyran-4-one (0.5 g) in ethanol (50 ml), glacial acetic acid (12 ml) and concentrated sulfuric acid ( 5 ml) was hydrogenated in the presence of 100 ngPd 10% on activated charcoal at 3.42 and rt and at 0 ° C for 6 hours.

The catalyst was filtered off, the acidic solution was neutralized with NH 4 OH, extracted with CH 2 Cl 2, dried and evaporated to give 0.3 g of 3,4-dihydro-3- (1-imidazolyl) -5-methyl-1-carboxylic acid. -fcenzopyran.

Elemental analysis: ........'-'-- '

Found / 0 67.1; H 5, OS; N, 12.0c

Calculated for: C 67, £; H, 6.13; N, 12.16

NtX (CDCl 3) δ ppm: 3.10 (1H, dd, -O-C 1 L-CH-CH) / h

3.42 (1H, dd, -O-Cp-CH-C-H)

H

3.20 (3H, s, -C-Oy 4.10-4.25 12h, m, -O-CR ₂ -CH-)

4.67 @ 1 H and, .- _0-CH2 -CH-)

... .delta., 60-7.64 (-6H, m, aromatics + imidasol) ,.

'48' -:

prepare the following compounds: (1-pyridinyl) -5-carboxy-1-tenzopyran;

Similar to 3,4-dihydrc-3- (

1,2,3,4-Tetrahydro-2- (1-imidazolyl) -7-cartoxynaphthalene,

1,2,3,4-trahyfiro-2- (1-imidazolyl) -6-carboxy-naphthalene, 2 ', 3', 4'-tetrahydro-2H- (1-imidazolyl) -7-methoxyxynaphthalene talen. ·· ^ 3-Top; 3-thromo-6 (7 g.), imidazole was kept at 60 ° C.

4H = 1-benzopyran-4-one is prepared as follows: n-ethoxy-2,3-dihydro-4 H-1-ene from pyr and n-4-one (E g) and Ν, Ν -dimethylformamide (200 ml) was added for 5 hours.

The solvents are npd-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p.

-vy-jae -CHgClg. -. (100..ml) ..,. .proniy is forgiving. extracts 8% ^HCl *

The acidic solution is neutralized with NaHCO 3, extracted

CH ~ C1 _O, dried and evaporated, yielding 2 g of 3- (1-imidazolyl) ώ * c 'O

2,3-dihydro-6-methoxy-4H-1-benzopyran-4-one, m.p. 150-152 ° C (EtOH 70%).

Ε4Ε (CDCl 3 ppm: 3.65 H 3H, s, -O-CH 2 ...... ........).

- - · - ------- - -4,7 - (2H, -. Ni. ^ - ^ 0-C-CH <). "" _R __________. 5.04 (1H, m, -0-CH ₂ -CH <) '<6.9-7.6 (6H, m, arom. + Imidazole).

Example 5

A mixture of 1,2-dihydro-3- (1-imidazolyl) -6-cartoxynaphthalene (1.6 g), palladium 10% on activated carbon (0.3 g), ethanol 99% (70 ml), glacial acetic acid ( 30 ml) ^and concentrated hydrochloric acid (5 ml) were hydrogenated for 12 hours at room temperature in a low pressure hydrogenator. Farr-Burgess type apparatus at an initial pressure of 3.42 nm.

At the end of this time, 96% of the theoretical amount of hydrogen was absorbed. The catalyst was filtered off, the solvent was evaporated, and water (50 ml) was added to the residue, yielding 1.3 g of 1,2,3,4-tetrahydro-2- (1-imidazolyl) -7-carboxynsphthalene hydrochloride. , tt 2 ° C

Elementary analysis:

Found: C, 50.08; H, 5.37; N, 5.65; Cl, 12.54. Calculated for C ₁₄ H ₁₅ ClN ₂ O ₂ :. C, 60.32; H, 5.42; N, 10.05; Cl 12.72 TLC, eluent CHCl ₃ : CH ₃ OH: CH ₃ COOH (170: 30: 1.5)

~ ~ 0.26

N43 (DiiSC-dg). <Tppm: 2.34 (2H, α, δ.-δ, -ΟΗ-)

3.03 (2H, m, _CH2 TCK -CE- ₂₎

3, I2H, 'm, = C-CH ₂ -CH-); _; <4, εε- (1Η, m, CH ₂ HH-CH ₂ -) · '.

- 7.30-9.30 (7H, m, r COCH + aromatics + imidazole)

IR (2r) ^ 0 = 0 169c ¹ cm

The following compounds were prepared in the same manner: cis-3,4-dihydro-2-methyl-3- (1-imidazolyl) -6-curboxy-1-tensopyran hydrochloride, m.p. Mp 226-235 ° C.

Elementary analysis:

Found: C, 56.2; H, 5.23; N, 9.10; Cl * .11.89

Calcd. For C ^ HH ^ Oy OyHHCl 57C, 57.05; H 5.13; N, 9.50pCl 12.02: κH (CDCl ₃ ) r rppm: 1.17 (3H, d, -C -C)

3.25-3.67 (2H, m, -O-CH-CH-O-) (4.70 (1H, m, -O-CH-CH-))

5.23 cm, m, -O-CH-OH-)

6.93-9.10 (6H, m, aromatics + imidazole) IR (K3r) NH ⁺ H) 2600-2300 cm @ ^-1 (OH) carboxylic acid 3000-2300 cm (0 = 0) carboxylic acid . 1700 cm ^x , (C-OC) 1250 cm ¹ .

Flashing of 1,2,3,4-tetrahydro-2- (1-imidazolyl) -naphthalene hydrochloride with a stechiosetric amount of NaHCC- yields 1,2,3-, 4-tetrahydro-2- (1- imidazolyl) naphthaler * .tt 95-98

Elementary analysis:

Found: O 76.26; H, 7.16; N, 13.81

Calcd. For O 78.75; K 7.11; N, 14.12

TLC, eluent ΟΗ, ΟΙλ: CH.OH (170: 30).

C o

3? = 0,57,

NL3 (CDCl3 cTppm: 1.97-2.5 · 12H, m, '= C-CH ₂ -CK-CH ₂ -CH ₂ -)

2.96 (2H, m, = C-OH, -CH-CH 2 -CR 3 -)

3.26 (2H, m, = C-CK ₂ -CK-CH ₂ -CH ₂ -)

4.46 (IR, m, C-C 1 -C-CK-CE 4 ClV)

7.03-7.62 (7H, m, aromatics + imidazole).

When the 1,2,3,4'-tetrahydro-2- (1-ethoxy-1-imidazolyl) -7-methimidazolyl) -7 * methoxynaphthalene hydrochloride is precipitated with NaHCO 3 -thiothium chloride, 1.2 is obtained. , 3,4-tetrahydro-2- (oxyn & ítalen. · .- 'ementérrií. · .analýza; - ^Λ poured Zeno / C 73,14 ;; Ή ^6.95;' N 12.21 _{iTypočteno-n} for C 73.75, K 7.06, N 12.27

TLC, eluent CHCl 3 / CH 2 OH (190: 10)

Rf = 0.31 '^? 0ΟΕΟ1γ-λ) - ^ ρρΕΐ: _2 ^ _τ 22 ί2Η, ^ ιπ "Ο.Η ₂ -ΟΗ ηΟΤΕ ₂₎ _ ^ _ ^ _ ^^ _2,86 (2H, m, CHg-CHg-CH-)

3.20 '(2H7 m, -CH ₂ -CH -) ....... ..........

. 3.76 (3H, s, CH ₃ C -) .............

4.40 (1 H, m, -CE-)

6.61-7.78 (6H, m ·, · aromatics + iidazole ·) ·. .Analogically after treatment with a stoichiometric amount ". The following compounds are obtained with NaHCO 3:

3,43-dihydro-3- (1-imidazolyl) -6-methoxy-1-cenzopyran,

3,4-dihydro-3- (1-imidazolyl) -6-carboxy-1-tenzopyran, 3,4-dihydro-2- (3-pyridyl) -3- (1-imidazolyl) -c-carboys -l-benzo pyran.,

1,2.3.4-tetrahydro-2- (1-imiaazolyl) -S-cartoxynaphthalene,

1,2.3.4-tert-Hydro-2- (1-inidazolyl) -7- (2-carboxyisopropoxy) naphthalene

2- (1-imidazolyl) -5-cyano-indan,

2- (1-imidolyol) -5-carbeyymethyloxyindane and .....

1,2,3,4-tetrahydro-2- (1-imidazolyl) -7-carboyymethylnaphthene.

Example 6

A mixture of 1,2-dihydro-3- (1-inidazolyl) -6-hydroxynaphthalene (1.85 g), potassium tert-butoxide (1.17 g), ethyl bromoacetate (1.12 mL) and tert-butanol (50 mL). ml) was refluxed for 4 hours.

The organic solvent was evaporated under vacuum and the residue was treated with water (100 mL) and CH ₂ Cl ₂ (100 mL). The organic layer was separated and washed with brine, dried over anhydrous K 2 SO 4

- 51 evaporated under reduced pressure. The crude product was purified by silica gel chromatography (solvent: CHCl 3 / CH 2 O, OK 160: 20), thus j ->

1, 2-dihydro-3- (1-imiaazolyl) -6-ethoxycarbonylaethyloxynaphthalene is obtained as an oil.

.. Elementary analysis: i- · .. ·.

Nfilezenof-0465 ^ 3.5.1 ^ -4-6, έΐ -Ν ^ ^'9.35:. <.- ^r ' ^r

Calculated for '_0'; C, 66.44; H, 6.65; N, 9.39

NKR (CDCl3, tppm: 1.29 (1H, t, CIL-CX-)).

2.6-3.1 (4H, n / c-CH ₂ -CH-).

4.24. (2H, q, CH 2 Crk)

4.56 (2H, s, O-CH ₂ -CCO)

6.44 (1H, br, -CH = C-)

6.67-7.80 (6H, m, aromatics + imidasol). Similarly, the following compounds are prepared:

1,2-dihydro-3- (1-imidazolyl) -6- (2-ethoxycartones lisoprbpoxy) naphthalene, g

TLC, eluent CHCl 3 / CH 3 OH (180: 20). . *

Rf = 0.75.

NMR (CDCl 3) c pppm: 1.26 (3H, t, CH ₂ , -CH ₂ )

1.57 (6H, s, (CH _{3) 2} C <)

2.63-3.1 (4H, m, -CKg-CHg)

4.23 (2H, q, --Cr @ 4 --CH.sub.6.41 (1H, br 9, --OH = C -))

6.63- 7.60. (6H, is, 'aromatics' + imidazole). The following compound is prepared analogously by reaction with X-bromoisobutyric acid:

1,2-dihydro-3- (1-imidszolyl) -6- (2-carbovyisopropoxy) naphthalene.

Example 7. A solution of 1,2-dihydro-3- (1-imidazolyl) -5-ethoxycarbonylmethyloxy-naphthalene (1 g) and 1 N 2N methanolic hydroxide. Potassium hydroxide (25ml) was refluxed for 4 hours. The organic solvent was evaporated under vacuum and the residue was rdz. release in water (10 ml). The solution was acidified with acetic acid, the solid precipitate was filtered off and washed with water to give SCO mg of 1,2-dihydro-3- (1-imidazolyl) -6-carboxynethyloxynaphthalene, m.p. 106-106 ° C (dec.).

Elemental analysis:.

Found: 66.53; H, 5.21; N 10.2? '..........

Calcd for C 24 H 25 N 3 O 6: C 66.65; H, 5.22; N, 10.36

TLC, eluent. CHCl ₃ : CH-OH: CH COOH; (40: 10: 2.5); .

Rf = 0.36 '

Nfc-R (DASO-dg) m / z ppir: 2.85 (5H > s, -OK ₉ -C? L)

4.65 (2H, e, O-CH2-COOH-) .....

6.60 (1H, br s, -CH = O-)

5,5S-c, 15 ^ C 6 H 7 ', a linear azoleX line

IR (KBr). .C = 0_ .. 1735 -cm ^-1 .Analogickým procedure the following compounds are prepared

1,2-dihydr 0-3- (1-imidazolyl) -6- (2-carboxyxyisopropoxy) naphthalene, mp 206-209 ° C _; ....._...........

Jftementární ^of analysis:

Found: -0.68-55: - H 6.11; N, 8.97 ........> 7th calc. - for -? H? GNgO?: C - 68, · 4 €; -H-6, G8; -4 «- 9.3 9

TLC, eluant CHCl? CH ^ ^ ^ OHsC COOK (40: 10: 2.5) Rf = 0.69 m ~ (WS0-d₆) ppm T ~: ^'l 50 í6H? . ... '2.85 HH,

6.65 (1H, s 6.60 to 8.11, (CK ₃₎ GC)

With 3, -c £ --ch '-) ’£ cL

Se, -CH = C- (6H, k, aromatics + imidazole),

3-Λ 1 - imi da z ol y 1) -6 -k ar bo ’y * y- 2-4-1-be nzopyr and n,

3- (1-imidazolyl) -6- (2-carboxyisopropoxy) -2H-1-tenzonyran,

3- (1-ifficazolazol) -6- (2-carbaxinyl) -2H-1-benzenesene,

methyl-3- (1-imidazolyl) -6-carboxy-2H-1-enzopyran, 2-methyl-3- (1-imidazolyl) -7-carboxy-2H- l-tenzppyran,

2-methyl-3- (1-imiazolyl) -6- (2-methyl-3- (1-ino-isoyl) -6-

(f-zopyran, • carboxyvinyl) -2 (1'-benzopyran, carboxypropoxy) -2H1-ben2-isopropyl-3- (1-imidazolyl) -6-carboxy-2H-1-benzopyran; -cyclopropyl-3-yl-3-azido-6-carboxy-2H-1-benzopyran, 2 ^L (3'-pyrrolidin-3-yl-1H-azazolyl) -6-carbonyl-2H-1- bens.opyran,

3,4-dihydro-3- (1-imidazolyl) -6-carbovy-1-benzopyran,

3,4-dihydro-2-methyl-3- (1-indazolyl) -6-carboyyl-1-benzopyran, *

3,4-dihydro-2-methyl-3- (1-imidazolyl) -6- (2-carboxyvinyl)

1- tenzopyrine,

3,4-dihydro-β-1,3-pyridyl) -3- (1-imidazolyl) -6-cartoxy-benzopyran; .. '...... ....... . · ....

1,2-dihydro-3- (1-imidazolyl) -7-carboxamide,

1,2-dihydro-3- (1-inidazblyl) -5-carboxy-naphthalene,

1,2- dihydro-3-il-imidazolyl) -S-carboxynaphthalen _t ..

£ -dihydro-3- (1-imidazolyl) -8-carbodox, n-phthalene,

1,2-dihydro-3- (1-iidazolyl) -5- (2-carboxyvinyl) naphthalene,

1.2.3.4- tetrahydro-2- (1-imidazolyl) -7-ksrboxynaftalon ^{1> 2} »3,4-tetrahydro-2-IL-iaidazolyl) -6-kartoxynaftalen,

1,2.3.4-Tetrahydro-2- (1-imidazolyl) -7- (2-carboxyisopropoxy) naphthalene

1.2.3.4- tert -hydro-2- (1-imidazolyl) -7- (2-carboxyvinyl) naphthalene

1,2,3,4-trahydro-2- (1-imidazolyl) -7-carboxymethylnaphthalene,

2- (1-imidszolyl) -5-carboxyindene

2- (1-imidazolyl) -5- (2-carboxy) Dindene a

2- (1-imidazolyl) -5-carboxyindane.

Example 8

Absolute ethanol (14.4 mL) was added slowly to SOCl 2.

(2.2 .ml) at 0. C and the mixture was warmed to room temperature and 1,2-dihydro-3- (1H-imidazolyl) -6-cartoxynaphthalene (7 g) was added. The reaction mixture was heated at reflux for one day and then stirred overnight at room temperature. Solvent and excess SOCl 3; It was evaporated under reduced pressure and the residue was chromatographed on silica gel using CHCl 2 CH 3 OH (50: 5) as the wash. 1,2-Dihydro-3- (1-imidazolyl) -6-ethoxycarbonyl-naphthalene is obtained (6.6 g, mp 113-116 ° C).

Elementary analysis:

Found: C, 71.50; H, 5.82; N, 10.50.

Calcd. For ^C 7 H, 64; R 5.97; M 10.45

TLC, eluent CHCl. CH: CH (50: 5), [alpha] F = 0.74. [.alpha.] D (CB-Cl2) cTppm: 1 → 62 (3H, t, CR, -CH2-). ; 2.80-3.40 (4H, .m,.-ΟΚ,.-ΟΗ.-Ο ^ λ,

4,3? (2H, Q, ΟΚ, -ΰ-Ο <-ta

AND!

~ '. ’6, $ 2 (1H, s, -CH =)

7.26-6 (6H, m, aromatics + imidyl).

Similarly, the following compound is prepared:

1,2-dihydro-3 &apos;-( 1-phenylthiazolyl) -6- (2-ethoxycarbonylmethyl) -1-naphthalene. * 0 * m? - /> ». · '...... · .. * · · *.

len./; · \? ''.

^: Elemental Analysis: "''

Found C, 72.81; H, 6.07; N, 9.45

Calcd. For C 73.4.7; ΙΊ 6.12: N 9.52TLC, eluant ”CHCI ^ CH ^ CH (90:10)

-, —_ —.-........... _: —_y _-_ _MlH ._ (. CDCl-) _ cCppm.:....1, .32_ \ 3H, .t, CH3 * 4

2.65 to 3.20 (4H, m, CH ₂ -CH _£)

4.26 (2H, q, CH 2 CH-j)

6.40 (1H, d, Ch = CH-COC) 6,55 (ΪΗ, W1CH = O-N

Jl

7- [1-9.9 (6H, m, boronates - + imidol)]; 7.16 (1H-ar-cHsCH-coc ·) -> Example 9

SOCl ₂ (2 mL) was added to a suspension of 1,2-dihydro-3-β-iodolyl) -6-carboyynaphthalene (500 mg) in D & F (10 mL). The reaction mixture was allowed to stand for 12 hours.

The ammonium salt is filtered off and ethyl alcohol is added to form a residue. precipitate, which is the chromate of the gutter. it is washed on silica gel with CHCl-: CEhOE: CE-: COOH (45: 5: 2.5). 350 mg of 3 [mu] l are obtained

1,2-dihydro-3-yl-imidazolyl) -6-carbamoyl-naphthylene.

,: _CH-; OE (50: 5) to -0.45  : 2.06 (2E, t, Γ · υ -P Ϊ at '0' .3,11 ' (2H, t, £ 4. nu - ^ p -r = 6.76 I1H, s, -CE =) 7,06- Δ, 0.6 (5H, m, aromatics) 10 f v kC = C)

3520-3410

LS m / e 239: (&) ·

- 55 In analogy to ss, the following compound is obtained:

2-methyl-3-yl-imidololyl) -6-carbamoyl-2H-1-benzopyran.

tříklcd 10; '' /. '\. t ^Λ i. The suspension (LiAlH 4 (&lt; 202 mg) in dry TEF &lt; 2.4. ml) was added dropwise at 0 ° C under a nitrogen atmosphere a solution of 1,2-dihydro-N-imidazoles-D-S-ethoxycarbonylnaphthalene (2.0 g) in dry TiCl 2. (22 AD). The reaction mixture was boiled under reflux for 1 day and then stirred overnight at room temperature. Water (40 ml) was then added to the mixture and the resulting precipitate was filtered off. The filtrate was concentrated, extracted with CHCl 3, dried (Na 2 SO 4) and evaporated under vacuum to give 1,2-dihydro-3- (1-imidazolyl) -6-hydroxymethylnaphthalene (2 g), mp 66 ° -91 ° C

Elementary analysis:

Found: C 74.00; H, 6.13; N, 12.03

Calcd. For C 74.33; H, 6.19; M, 12.39

TLC, eluant CHCl3 (50: 5), Hf = 0.29 NříH (CLC1-) <Γ ppm: 2.60 (4H, O, CH _n -CH ( _O ) c c. 4.60 (2H, WITH, CH ₂ -OH) 5.26 Í1H, WITH, -OH) 6, 40 Í1H, ² > -CH =) '... 7,06- 7.63 t X k.c; i, m, aromatics

Example 11

Ns 1,2-dihydro-3- (1-phazoloyl) -o-methoxynoiethylene was treated with an equilibrium amount of hydrogen chloride to give 1,2-dihydro-3- (1-imicazolyl) -6-methylcynaphthyl hydrochloride, tt Mp 70-72 ° C

TLC, eluent. : CH.CH (160:20) HF = 0.61

2.92 Í4H, 7.10 (1H, s s 6,77- -6.27 (cH 9.65 Í1H, š s

'-'56 Example 12.? '' '' *.

Atletes, each weighing 150 mg and containing 50 active ingredients, are produced as follows:.

- • -Mixing passed 000 -table:, '.... *. ..

1,2-dihydro-3- (1-etidazolyl) -6-carboxy-naphthalene _: 500 g lactose, 710 g _t . Corn starch 237,5 g

Rectangular 37.5 g of magnesium stearate, 1,2-Dihydro-3- ( 1-Imidazolyl) -6-carboyynaphthalene, lactcza and half of the maize starch are mixed, and the mixture is then passed through a 0.5 mesh sieve. mm, Corn starch. (18 g) was suspended in warm water (180 ml). The resulting paste was used to granulate the powder, which dried, dried in a 1.4 mm sieve and then added the remaining amount of starch, talc and magnesium stearate. Carefully, mix _ and _Upper can be used in tablets, using punches with a diameter of 8 mm.

wherein _____ represents a single or double bond, 2 complements a single bond or 2 does not represent an oxygen atom or a group -CHg-, each of the substituents R ^, ^s ^ 4 »which may be the same or different, modified (a) a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, a C 1 -C 6 alkyl, a C 1 -C 6 alkoxy, acyl or

C ₂ -C 4 acylamino, -SR 1

-Μ / Γ. . -COR 4 -COR or

Where A is. -O'r '’or -n /” and every A * netp Ř that are

X.lfl same? Or different, means)) one of A ,, U, R-, and x ’i’

A selected 2 -COCiLCR *, - CH-C-COR hydrogen, or 4 is .5-tetramethyl R and -X-C-COA, wherein:

R

C 1 -C 8 alkyl, or yl or a group

A, A * and A have the above meanings, and X is -C-, -? - or -NH-, and the others -. The substituents are as defined in (a). one of R _c and R _r is hydrogen and the other is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl or a phenyl or pyridyl ring, wherein the phenyl or pyridyl ring is unsubstituted or substituted by one to. three substituents selected from hydroxy--

and C 1 -C 4 alkyl, and its pharmaceutically acceptable salts.

2. Compound. of formula I according to claim 1, in which? symbol means double vssb, · - .....

Z is as defined in claim 1, • ^·. each and each of which may be the same or different, ·. • hydrogen, hydroxy; halogen, C 1 -C 4 alkyl, i

C.-Cg slkozyskupinu, -CH-CH -CCGR -CONk or ^8, wherein each X 4 * £ -¾ _R of B and _T is independently hydrogen or C ^ -C ^ alkyl, or

(B ') one of R p R ₂ , H, and R ₄ is C 8 -C 6 cyi, -C 6 C 6 O 10

-OC-COCR, '-OC-CON ^and | R

AND

Ν 'Bx • Rv and ^{R 3} and <^ ^a ~ --- A-CH = or -CH = CCOÍL CON. / ⁸ ®. R. wherein R ^c iL -, and _R are as definované'významy-and-other-sutati-. The substituents have the meanings given under (a), one of R 6 and R 8 is hydrogen and the other is hydrogen -C 1 -C 4 alkyl, cyclopropyl or a phenyl or pyridyl ring, substituted with or substituted with one to three substituents selected from hydrby-acyloxy, and C ₂ -C elkoxyskupiny, and pharmaceutically acceptable salts thereof. '.

A compound of formula L according to claim 1, wherein the kZ1IZ symbol is a double bond sensed,

Z represents an oxygen atom or a group rCH _n -, one of R 1, R 1, and B 1 is -CCCR. where R is my ^ hcr-'Λ dsfi

The same meaning as defined in claim 2 and the other substituents are independently selected from hydrogen e hydroxy, one of R- and R 6 is -CONH 4, -CH ₂ CH, -CCCH 3, a, and, and

-CE..COOR, -CH = C-COCR. , -CH = C-CQNH-, -O-C-CCCR or -O-C-CONE,. c and '- -' - -. of ' and I

R wherein R and R _{fe fl} význsm are as defined in claim 2 and the other substituents j3ou independently selected from hydrogen and hydroxy, '«' ·· Λ 'fV'

IC and R @ 1 are each individually hydrogen, and its pharmaceutically acceptable salt is hydrogen. ^c . salts.

/

A compound of formula I according to claim 1, wherein the symbol - represents a double bond,

... Z jykyslíkýhěbó / group -.- CH ^ - //. · ’·

-. -. i * one of R- ,, R. _? , R - and R. is -CC-CCR, wherein 'R * is -NH ⁴ ->^4' ge. ·% or -OR and R and R _v are as defined in claim 2 and θ dc the other substituents denote hydrogen,

R 6 and R 8 denote hydrogen, and pharmaceutically acceptable salts thereof

A compound of formula I according to claim 1, wherein the symbol - represents a double bond,

Z is -CH 2 -, one of R 1, R 2, R 1, and R 1 is -COR 1 -C 1 -COOR 4;

R. . . . ...

i ®

-CH-C-COR., Wherein R _a is as defined in claim 2 and R m is as defined in claim 4 and the other substituents are independently selected from hydrogen and hydroxy;

R @ 1 and R @ 2 are hydrogen, and pharmaceutically acceptable salts thereof

A compound of formula X according to claim 1, wherein the yg symbol— · represents a double bond,

Z is one of R 1, R 1, 3, and R 1 is -COR, wherein R is as defined in claim 4 and the other substituents are hydrogen,

R @ 1 and R @ 2 denote hydrogen, and pharmaceutically acceptable salts thereof. 1,2-Lihydro-1- (1-imidazolyl) -6-carboxy-naphthalene, C 1 -C 4 -alkyl esters, and pharmaceutically acceptable salts thereof.

1,2-Lihydro-3- (1-imidazolyl) -6- (2-carboxyisopropoxy-) naphthalene, C 1 -C 6 alkyl esters and pharmaceutically acceptable salts thereof.

9. 1,2-Lihydro-3- (1-imidazolyl) -6-carbamoylnsophthalene a

60 'a pharmaceutically acceptable salt thereof.

10. A compound selected from the group consisting of: 3- (1'-imidazolyl) -2'-benzopyran, 3- (1-imidazolyl) -6-chloro-2H-1-benzopyran, v _; .

3- (1-Methylphenyl) -6-hexyloxy-2H-1'-benzopyridine. ^'R 3- (l-iniďazólyí) -6-carboxy-2H-I-tenz6pyřah ^-; F;

3- (1-imidazolyl) -6- (2-carboxyisopropory) -2H-1-benzoryran,

3- (1-Imidazolyl) -6- (2-carboxyvinyl) -2H-1-tenzopyran, 2-methyl-3- (1-imidazolyl) -6-E: ethoxy-2H-1-benzopyran, ~ 2 -methyl-3- (1-icazolazolyl) -6-carboxy-2H-1-tenzopyran;

2-Methyl-3-yl-1,3-azazolyl) -7-carboy-2H-1-benzopyran,

2-methyl-3- (1-imidazolyl) -6-carbanyl-2H-1-tenzopyrane, 2-methyl-3- (1-icidazolyl) -6- (2-cartoxyvinyl) -2H-1-benzopyran, 2-methyl-3- (1-imidazolyl) -6- (2-carboxyisopropoxy) -2H-1-benzopyran,

2-isopropyl-3- (1-imidazolyl) -6-carboxy-2H-1-benzopyran,

2-methyl-3- (l-imidazolyl) -6- ^r ethoxycarbonyl-2H-benzopyran, 2-cyclopropyl-3- (t-iniidazoiyl) -6-carboxy-2H-ténzopyran _J 2- (3 4-dimethoxyphenyl) -3- (1-imidazolyl) -6-methoxy-2H-1-benzopyrrine,

2- (3,4-dihydroxyphenyl) -3- (1-imidazolyl) -6-hydroxy-2H-1-benzopyranp

2- (3-pyridyl) -3- (1-imidazolyl) -6-cartoxy-2H-1-benzopyran, 2- (4-hydroxyphenyl) -3-1H-imidazolyl) -5,7-dihydroxy-2K-1-benzopyran ,

3,4-dihydro-3- (1-thiazolyl) -6-cartoxy-1-benzopyran, 1,4-dihydro-2-methyl-1- (1-inidinolyl) -5-carboxy-1-tanzopyran, ,, 4-Dropyr-2-methyl-1- (1-imidazolyl) -6- (2-carboxamides) 1) 1-Banzopyran,

1,2-Dihydro-3-yl-iffidazolyl) naphthalene

1,2-dihydro-3- (1-imazolazolyl) -6-methoxyphthalene;

1,2-dihydro-3- (1-imidszolyl) -7-methoxynsphthalene,

1,2-dihydro-3-l-imidazolyl) -6-methoxy-7-bromonaphthalene, 1,2-dihydro-3- (1'-imidazolyl) -6-methoxynithalene, 1,2-dihydr q-3 - (1-imidazolyl) -6-ethoxycarbonyl, 1,2-dihydro-3- (1-imidazolyl) -6-hydroxymethylnaphthalene, 1,2-dihydro-3- (1-imidazolyl) -7-carboxynaphthalene ,

-.61 -.1, 2 - δ i by d r o - 3 - i 1 - i m i <2 and z o l 1) - 5

1.2- d i hy d r c -3 - i 1 - i d a z o l 1) - 5

1,2-dihydrogen-3-i-1-i-zenylyl) - 5 kur boxynaí t a 1 an, k ^bacoylnaphthalene, boxykrty nylmethyloxy naphthulene,

1,2-dihydro-3- (imidazolazolyl) -5-12-ethoxycarbonylisopropyloxy) naphthalene; ... 'h *'. <- with - *. , · * · I i.. ·. , .. K 2 .J ...

2-Dihydro-3- (1-iidazolyl) -6-carbororylsyl oxynaphthalene,

1,2-dihydro-1- (1-imidinylolyl) -6- (2

1,2-dihydro-1H-imidazolyl) -6- (2-carboxylic acid naphthalene, ethoxycarbonylvinyl) n-phthalene,

1,2-diyl-3- (1-imidazolyl) -6-hydroxy-7-acetylnaphthalene,

1,2-dihydro-3- (1-imidazolyl) -6-hydroxy-7-carboxy naphthalene,

1,2-dihydro-3- (1-imidazolyl) -6-tert-butyl-7-hydroxynaphthalic acid,

1,2-dihydro-3- (1-imidazolyl) -6-carboxymethyl-naphthalene,

1,2-dihydro-3- (1-imidazolyl) -8-carboxynaphthalene,

1,2,3,4-tetrahydro-2- (1-imidazolyl) -7-carboxynaphthalene,

1,2,3,4-tetrahydro-2- (1-imidazolyl) -6-carboxynphthalene,

1,2,3,4-tetrahydro-2- (1-imidazolyl) -7- (2-carboxinyl) naphthalene,

2- (1-imidazolyl) -5-carboxyindene a

2- (1-imidazolyl) -5- (2-carboxyvinyl) infiene, their pharmaceuticals; ^of acceptable sow and, as appropriate, of C ^ -C ^ alkyl '..estery *

A process for the preparation of compounds of the general formula of claim 1, characterized in that. that čenir.a general vsorco II

Irodle se,

Claims (4)

in which . . ^ 2 ^»á 3>'V' ^ 5», ^ -2 ^and 6 have the meanings given in claim 1 and then is hydrogen or aeylqvou group is converted to a compound of formula I in it? 3, Κ ₅ , R- _, phy and Z are as defined in claim 1 and 3333 means - a double bond, or - (fc) a compound of formula (II), as defined above, which is defined as being a yee. the compound of formula (1), in which Rg and 2 have the ridges shown in claim 1 and the symbol 3333 means a single bond, or c) reduces a compound of formula III, cm) - - -fy- · fy Ry, _R4, Rg and -fy. Majífy second známydefinované in bodě- · 1st - No Iaz - the - Z-i typist _at col UOC Enina _ obecné.hpjv of CE or _I., _ in kterém'fy'fy fy fy fy Rg and 2 have the meanings defined in paragraph 1 and the symbol 3333 indicates a single bond, or --- · d) -ireduku ^ e ^ e ", Compounds of the _general-T -v2.orjee_iy ____ CIV) in which. R, R ~, R-, R- ,, Η, R₆ and Z are významy'uvedené in claim 1, to give a compound of formula I, wherein R ,, R ,, 'fy R, R _fi, R 6 and Z have. the meanings given in claim 1 and the symbol 3333 represents a single bond and, if desired, a compound of formula I is converted into another compound of formula I and / or, if desired, a compound of formula I is converted into a pharmaceutically acceptable compound thereof. the salt, and / or, if desired, the salt is converted to the free compound, with / if necessary, the E isomer is separated into the individual isomers. ·. 12. A pharmaceutical composition comprising a suitable carrier and / or diluent and an active ingredient, a compound of formula (I), or a pharmaceutically acceptable salt thereof. A compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof, other than a compound wherein one of the substituents x, X, A, and C is -C-C3 *. B. A ', wherein A *, A' and A are as defined in claim 1 and three of the other A 1 substituents. A, R m and 3 have the meanings defined in claim 1 for use as an inhibitor of thromboxane A2 synthesis and a prostacyclin synthesis stimulant. A compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof, wherein one of the substituents ϋ _χ , U ', ^ 3, ^ ^ and 4 ₄ is -O-C 3' -CO 3, wherein A ', 3 and A have the meanings defined in claim 1 and three of the other 3 _χ , 3 ₂ ^and R 3 have the meanings given in claim 1 for use in the prevention or treatment of atherosclerosis dislipidaemiézy. A process for the preparation of a compound as defined in claim 1, or a salt thereof, substantially as described A pharmaceutical composition as in Example 12. of formula (I), as defined in claim 1. acceptable in any of the examples! 11 to 11 is essentially described above Descending :. 7 / ^Η ·.